Selecting for intelligence feels likely to be banned (unfortunately as this could be hugely beneficial for humanity if widespread) but in theory selecting against disease should also be pro intelligence as both are correlated through mutational load, right?
Given the prices involved here and methods used, this might be...really difficult to ban? If you let parents see each embryo's data before they make a choice, and the information necessary to make that selection is on SciHub, then, uh, *wink wink*...
Would be hard to ban any use of this method considering how many diseases it can fight (and how sympathetic people suffering from these diseases are), and I think any use of this method quickly results in selection for whatever parents want (whether that's intelligence or aesthetic traits).
Yeah, I agree. In fact, I don't know if you even need the data. Here's an article I saw linked over at marginal revolution a while back:
"Children resulting from frozen embryos were more socially adept than those implanted fresh after eggs were fertilised. The children also moved better, had superior communication skills and showed more independence. Allan Pacey, a fertility expert at the University of Sheffield, suggested that this was caused in part by the rigours of the thawing process. Not all embryos survive thawing, and perhaps those that do are “stronger”, he said.[11] Perhaps freezing and thawing embryos is an inadvertent eugenics process, most successful with embryos having a low mutation load."
There does seem to be a selection process, post implantation.
"Good obstetric outcome (GBO), defined as a singleton, term, live birth with appropriate for gestational age birth weight, was the primary outcome measure. Secondary outcomes included live birth, clinical pregnancy, spontaneous abortion, preterm birth, multiple births and gestational age-adjusted weight. Outcomes were modeled using the generalized estimating equation approach.
MAIN RESULTS AND THE ROLE OF CHANCE
"Overall, fresh transfer was more likely to result in a live birth (55.7% versus 39.5%; adjusted risk ratio 1.21; 95% CI 1.18–1.26; P < 0.001). "
Well, I'm not sure they're not entirely "opposite" results. If freezing meant embryos with problems were less likely to develop to term that would explain the improved health outcomes from frozen infants.
I'm saying that in contrast or addition to the Marginal Revolution advanced hypothesis "Not all embryos survive thawing" it could be that thawed embryos with health issues are less likely to be delivered to term.
If the observations are all accurate then I really wonder what mechanism mediates this.
That makes me wonder-- is freezing merely a mechanism to improve outcomes for IVF, or can it be used to improve outcomes even relative to non-IVF natural conception?
That is, would it make sense for couples to freeze embryos specifically to filter out worse ones (aside from the usage of PGS)?
If it's banned in the US but legal in, say, Brazil, then presumably a lot of wealthy ambitious couples will go on a long vacation (or several short ones) in Brazil and come back with the woman pregnant, and regulators in the US unable to do anything about it.
Citizen jurisdiction. They might not be able to force the woman to have an abortion ("cruel and unusual"), but a country can absolutely throw its citizens in prison for what they did abroad.
(The USA in particular also has some really dodgy long-arm statutes which give them jurisdiction if any money touched the US banking system at any point.)
I hope the Overton window shifts enough that selecting for intelligence gets accepted -- I always think of this passage by Nick Bostrom in https://www.nickbostrom.com/views/science.pdf:
"There are three ways to contribute to scientific progress. The direct way is to conduct a good scientific study and publish the results. The indirect way is to help others make a direct contribution. ... A third approach is to marry the first two and make a scientific advance that itself expedites scientific advances.
A “superficial” contribution that facilitates work across a wide range of domains can be worth much more than a relatively “profound” contribution limited to one narrow field, just as a lake can contain a lot more water than a well, even if the well is deeper.
No contribution would be more generally applicable than one that improves the performance of the human brain. Much more effort ought to be devoted to the development of techniques for cognitive enhancement, be they drugs to improve concentration, mental energy, and memory, or nutritional enrichments of infant formula to optimize brain development.
Imagine a researcher invented an inexpensive drug which was completely safe and which improved all‐round cognitive performance by just 1%. The gain would hardly be noticeable in a single individual. But if the 10 million scientists in the world all benefited from the drug the inventor would increase the rate of scientific progress by roughly the same amount as adding 100,000 new scientists. Each year the invention would amount to an indirect contribution equal to 100,000 times what the average scientist contributes. Even an Einstein or a Darwin at the peak of their powers could not make such a great impact. Meanwhile others too could benefit from being able to think better, including engineers, school children, accountants, and politicians."
But interventions like salt iodization only help better realize potential, not increase it. It's the latter I'm curious about. Unfortunately this is a really really hard problem: https://www.gwern.net/Drug-heuristics
Practically, what's the difference between "realizing" potential and "increasing" it? Is it the upper bound of what's possible? I don't know if we know what that upper bound looks like for polygenic testing for either a given individual or a population.
Yes, the main difference is about the upper bound. Addressing iodine deficiencies (from the limited reading I've done) is likely to be a very cost-effective method to improve cognitive ability in the developing world. I think it's a shame we don't prioritize these types of low-cost interventions that have such huge long-term effects.
In regards to your second question, the upper bound for polygenic testing for a single generation is about 1 standard deviation for any given trait given current limitations on oocyte production and GWAS sample sizes. For most diseases it's closer to 0.3-0.5 standard deviations.
For multiple generations the limits are much much higher. For example, Steven Hsu has estimated that if you naively add up all the alleles that contribute positively to IQ, additive variance alone would predict that genome would have an IQ of about 1000. Obviously in practice that wouldn't work even if you could do it because at some point the relationship between positive alleles and phenotype would break down. But it gives you an idea of what might be possible in the future.
Further evidence can be found in animal and crop breeding programs that have been going on for thousands of years. We have increased the oil and protein content of the ancestors of modern corn by 30 standard deviations over the last 10,000 years. And while humans are not corn, many of the genetically influenced traits we care about (like disease risk) are controlled by a similarly large number of genes (meaning they are probably capable of undergoing similarly large increases with enough selection pressure).
"For example, Steven Hsu has estimated that if you naively add up all the alleles that contribute positively to IQ, additive variance alone would predict that genome would have an IQ of about 1000."
We seem to agree that that wouldn't actually work. So doesn't that indicate a problem with the model we're using? We do agree that not all improvements are additive, right? Some may just be different ways of accomplishing the same thing.
I feel like it's hard to predict whether this technique could produce people who were that much faster, better, or stronger than the best currently existing humans without some kind of tradeoff. Eventually we'd presumably start running into issues related to cranial capacity. Or trading off generalized for specialized intelligence.
The notion of "+.2 IQ points for this gene with no consequences or costs" just seems deceptively ... neat and predictable.
"Further evidence can be found in animal and crop breeding programs that have been going on for thousands of years. "
Sure. And the Green Revolution has accelerated that improvement with fertilizers, pesticides, watering, etc. It's also produced plants that don't survive well outside of a farm. It's produced plants that serve humans rather than themselves (since obviously wild plants have had millions of years to improve themselves for their own purposes.) Whats the equivalent of applying that metaphor to humans? Being able to use more fertilizer and water, as provided by farmers, is win-win. Maybe human intelligence can do something similar. More food = more cholesterol for neurogenesis? But then, we've demonized cholesterol and we give people drugs so they produce less of it so they can live longer. At some point crop improvements are going to have to hit some kind of physical limit in terms of photosynthetic efficiency and available light. Even if per hectare crop production is not yet leveling off for some crops. Monoculture offers a benefit in terms of being able to harvest ripe crops at a set time, reducing poaching by animals. But the loss of genetic diversity also increases vulnerability to pathogens. Genetic diversity exists for a reason. IQ positively correlates with alcoholism, for example.
An endurance runner has more slow twitch muscles. A sprinter has more fast twitch muscles. Once we eliminate various physiological defects, further improvements are tradeoffs. And I don't know how to be certain that this wouldn't be an issue with polygenic testing.
Polygenic testing is a very exciting development. It can help address things like increasing mutational load in an ethical fashion. But we're dealing with self modifying systems whose behavior we can't fully predict or understand. That seems like a setup for surprises.
I think talking about Overton windows is rather premature at this point, as there's no hard evidence that embryos can be effectively screened for intelligence at all. Merely assigning a numeric score based on a bunch of markers isn't very reliable for an extremely polygenic trait such as intelligence... especially when there's still active debate going on regarding what proportion of IQ is genetic; and even to what extent IQ correlates to real-world outcomes; or whether it even makes sense to use a single scalar quantity to answer such questions.
It’s 85 percent heritable (g), not iq scores. Especially at adult-age. Less suppressed variation due to being forced to go to school or parental choices. Cumulative exponential effects from learning faster and gaining skills faster. Same reason why bad diet in NKorea attenuates and reduces intragroup variation. Phenotypic variation is maximized and potential is realized when opportunities are maximized; sex-linked behaviours, career choices, intelligence, anything. Breeding dogs and animals have exact morphological similarities as hybridization of haplotypes or human breeding groups, it’s just politicized and suppressed because the repercussions are too big to be accepted (non-conscientious, psychopathic, low intelligence being a feedforward loop of more undesirable societal outcomes and offspring). And au contraries to the many individual variant effect hypothesis, it’s mainly few main progenitor genes with integrated mechanisms that are deterministic of neurological/biophysical health that are conserved with additional improvements made by a combination of rare and minute pathways that increase the efficiency/differentiation of brain tissue/change of rate of growth and thickening which increases the magnitude of intelligence gains. Not just a series of 0.00012 percentile variants that improve myelination or conductivity. dendrite dispersibility. Scalar measurements are invariant with respect to any and all cognitive tasks. More instructions, more complexity is inversely proportional to success rates; that includes taking medicine, making mistakes, accidents or anything. Statistical artefacts are also irrelevant and impertinent. China will be dominating and probably Israel too. The elite population has already been practicing eugenics discretely with IVF reiterated embryo selection and cross marriages stratified only by high conscientiousness, agreeableness, intellect and desire for dominance.
Judaism is bioethically permissive (abortion is legal in Israel, no one cares) and there isn't much wokeness, and there is a national defense reason to add +10 IQ to everyone so I expect them to be first or among the first to do embryo selection.
You don't have to understand all of the genes in order to select for higher intelligence. It may be extremely polygenetic, but we can still identify the gene variants with the largest effects and select for those. I think the Overton window is very relevant, since we're going to have the technology to attempt it long before we know whether it's actually possible.
To know if we can select for intelligence, we'd basically need to just do it on a massive scale in humans, then compare the IQs of children selected for intelligence to children not selected for intelligence (and obviously account for the many, many confounders). The question is whether we allow this experiment to take place or not.
> It may be extremely polygenetic, but we can still identify the gene variants with the largest effects and select for those.
As of today, we really can't do that, because intelligence is not just a linear combination of a bunch of genes. Like any polygenic trait, it's a complex network of interactions between genes and regulatory regions, all of which upregulate something while downregulating something at the same time. So assigning an IQ score based on a bunch of markers is not a simple matter of multiplying their association scores together. It's a search in multi-dimensional space, and the problem with brute statistical models -- yes, even ML models -- is that if you have enough dimensions, you have enough degrees of freedom to pretty much find anything you want.
As I said in my comment above, if someone had a model that provably selects embryos who then grow up into children who reliably perform better in the real world than controls, then I would be impressed. But merely throwing GWAS at the wall to see if it sticks is less interesting to me.
> Like any polygenic trait, it's a complex network of interactions between genes and regulatory regions, all of which upregulate something while downregulating something at the same time.
It's true of course that the genetics of intelligence are complicated. But you're incorrect in saying that this makes it impossible to select for. Most of the variance in highly polygenic traits can be explained with linear effect models. See this paper for a more thorough analysis: https://www.biorxiv.org/content/10.1101/2020.02.12.946608v1.full
> if you have enough dimensions, you have enough degrees of freedom to pretty much find anything you want.
Only if you use a weak statistical threshold for significance. But most modern genome-wide association studies use a very strict significance threshold of 5*10^-8, at which point you don't get many false positives.
> But merely throwing GWAS at the wall to see if it sticks is less interesting to me.
This is not an accurate description of how polygenic screening is done. All of the predictors used by companies currently doing pre-implantation screening are validated using test sets of siblings that weren't in the training data. And while the predictors used today don't capture all genetically caused variance (usually they capture around 20% of it), they do significantly better than chance at picking out the sibling who will go on to avoid developing a tested disease.
There are some limitations to these results (for example predictors of disease risk created with a training set of people with mostly European ancestry don't generalize well to non-Europeans), these limitations are essentially due to differences in the frequencies of certain alleles among populations whose common ancestors are sufficiently distant.
This in turn is caused by something called "linkage disequilibrium". When DNA from a sperm and egg crosses over during meiosis, the locations of such cross-overs are essentially random. But more often than not, base pairs on the chromosomes that are physically very close to one another on the genome will remain together after crossing over. This creates a problem for geneticists: if you're trying to figure out which letter in a protein-coding region is causing a 2% increase in risk of breast cancer, how do you know whether it's the A or the T right next to it? They're almost always inherited together due to linkage disequilibrium.
For people with recent ancestors, this doesn't have much of an effect on the prediction accuracy of these GWAS tests; the A and the T are very likely to be inherited together, so no matter which one was causing the increased risk of Breast Cancer, selecting against one will probably select against the other. But the longer ago two people last shared a common ancestor, the more likely it is that one of their ancestors had a split between those the letter that actually causes the change and the one that you've pinpointed as most likely to cause it. If that happens, your predictor becomes useless because it's incorrectly assigning causation.
Fortunately there's a solution. In the short term with the relatively small sample sizes we have today, we can restrict predictor use to populations in which they have been validated to work well. And in the longer run, GWAS need to start including genetic/phenotype data from a much larger, more genetically diverse group of people. Doing so will both improve the predictors AND make the benefits of embryo screening available to a larger group of people. And we're likely to develop many useful screening tests along the way that can be used to target health interventions at people most at-risk for certain conditions.
I don't think something has to be achievable for there to be a productive discussion about Overton windows. Five years ago self-driving cars were a novelty that still to this day don't function well enough for commercial use, but there were all sorts of ethical discussions around their decision making that helped create a societal opinion about the technology. Similar discussions take place all the time with the potential problems/benefits of AI and how we should approach the technology.
Boosting human intelligence through this type of gene selection is a bit further off than some of these things, but the potential is there for it to arrive within our lifetimes, and discussions about it will surely happen before it is fully feasible.
>Five years ago self-driving cars were a novelty that still to this day don't function well enough for commercial use, but there were all sorts of ethical discussions around their decision making that helped create a societal opinion about the technology.
I'm pretty sure that the "societal opinion about the technology" is that society expects the technology to produce cars that simply do not crash, and that nobody who matters is going to say "It's great that our cars make what we consider proper ethical decisions about who or what to crash into". The consequentialist nerds got to imagine that the Trolley Problem finally had a real-world application; everybody else said "if you're talking about what the car will decide to crash into, get back to us when you've got the car deciding not to crash".
We already know polygenic scores can predict which sibling has higher intelligence and educational achievement. Predicting which embryo will is no different.
If having 100,000 more scientists made a huge difference, we would *already* have seen that effect, since there are *way* more scientists working today than at any time in human history, even on a per capita basis. If it made a giant difference, we ought to be seeing Einstein/Fermi/Newton breakthroughs on an annual basis, certainly much faster than we saw them before 1939 -- and nothing could be further from the truth.
The entire calculation is based on a dubious premise about the nature of scientific advance, id est that it proceeds like some kind of construction of an earthen dam, and if you have 200,000 peasants with buckets it gets done 2x as fast as if you had only 100,000. But so far as I can see, an examination of history suggests quite the contrary, that science advances largely by abrupt and difficult to explain (let alone predict) highly contingent paradigm shifts that are the result of some lucky coincidence of improved instrumentation, cultural readiness for a paradigm shift, and some well-prepared brilliant mind that happens to be born at the right time in the right place. You might say it happens by quantum transitions, like absorption of an visible photon to cross a band-gap, and in such a case it doesn't really matter how many IR photons with energy much less than the band gap you provide, nothing happens until the big hv comes along.
> If having 100,000 more scientists made a huge difference
I think you're thinking of "huge" in relative terms, while Bostrom (and I) think of it in absolute terms. Like how a billion dollars is a huge amount of money, but negligible vs say Apple's market cap. I agree in relative terms it's small, especially given that (to quote Scott) "constant growth rates in response to exponentially increasing inputs is the null hypothesis" (https://www.lesswrong.com/posts/v7c47vjta3mavY3QC/is-science-slowing-down). It's still a lot larger than the first 2 sorts of advances, usually.
I agree with the content of your second paragraph, but am puzzled by how it wouldn't be affected by talent pool size (whether size = number of people or "amount of talent", eliding difficulties in aggregating talent for this to be measurable).
It's affected by the talent pool size up to the limit of saturation, but not afterward. Think of enzyme kinetics: once you saturated the enzyme, you don't get any more product by boosting the substrate concentration, because the substrate concentration is no longer the limiting factor on the rate.
So the question is: have we reached saturation on the talent pool yet? That is, is everyone who *can* do scientific breakthrough thinking identified, recruited, and remunerated sufficiently that the availability of talent is no longer the limiting factor? I think a decent case can be made for "mostly yes." You don't really see much in the way of Ramanujans escaping otherwise impoverished lives by sheer luck (writing a letter to Hardy). We're pretty darn good at identifying people who have the requisite smarts and easing their way into the field if they want to be in it. (With some caveats, of course: I'm amused that the woman who was one of the pair that invented the modified-nucleoside tech used to make the mRNA COVID vaccines had a rough time at Penn and ended up leaving because people thought she was an unproductive crank, and now there are people calling for her to share the Nobel for the work.)
That begs the question of what the limiting factor might be, if it isn't the size of the talent pool. As I said below, I don't have any strong ideas on what it is, other than some vague feeling that resources are not quite distributed right, that the *most* talented of the talent pool are getting the most time/money to do their work, a the expense of the less talented. (And here I mean "talented at producing breakthrough ideas.") But I have no idea how to identify such people algorithmically, although I tend to feel I can spot them when I meet them -- it's a certain weird independence of thought, an ability to spot the weakness in the conventional wisdom. It's the person who says "this phlogiston theory is all well and good, very logical and explains a lot, but I wonder what happens if I oxidize some mercury."
"A common theme across all of these is that fairly obvious opportunities were not pursued by incumbent institutions. We give examples of actions Fast Grants took not to indicate some kind of supposed brilliance but rather to emphasize the opposite: Fast Grants pursued low-hanging fruit and picked the most obvious bets. What was unusual about it was not any cleverness in coming up with smart things to fund, but just finding a mechanism for actually doing so. To us, this suggests that there are probably too few smart administrators in mainstream institutions trusted with flexible budgets that can be rapidly allocated without triggering significant red tape or committee-driven consensus."
For the sort of science that needs a research laboratory to be done properly, the limiting factor is probably the supply of research laboratories. Fully stocked, staffed, and maintained research laboratories are not cheap, and lots of people who aspire to be and have the education/credentials to be scientists seem to never land a position in one (except maybe as chief bottle-washer to a "real" scientist).
There's some science that can be done just by staring into a coffee cup and thinking real hard, https://www.beanthinking.org/?p=1019, or maybe poking at the keyboard of a commodity PC. But there's a great deal more science that deceptively seems like it should be this sort of science, but veers rapidly into junk if not grounded by experimental verification and model validation. For which, you need research labs, and if you exceed the research-lab limit you just wind up with lots of wannabe scientists thinking up junk science.
> I think a decent case can be made for "mostly yes."
I think it's "almost certainly not". The internal politics, incentives and funding structures around science are pretty perverse, and I think this drives a lot of talent away.
I would like to challenge your central premise: that we aren't seeing more scientific development than ever before.
Medicine is the classic example. Today there are people studying and creating scientific breakthroughs on rare diseases. We lay people don't see this unless we have a relation struck by this rare condition. These are really hard, breakthrough discoveries that save lives. Are they society changing? Yes, if it's your loved one.
Yes we haven't learned how to increase our rate of Einsteins (not sure I agree but I'll accept it), but the breadth across disciplines and niches that we are advancing human knowledge today is unprecedented.
I'm not sure, but I don't think I agree with that. If we consider advances in the context of what already exists, and the resources available for implementation, I think a strong case can be made that there are many periods of history in which general technological advance was significantly higher -- and was reflected in a much strong rate of general social improvement. Let's say the advances in chemistry, thermodynamics, engineering, metallurgy and civil engineering in the 1600-1700 timeframe, for example. Or even the advances in physics in the 1880-1950 timeframe.
I agree biochemistry or molecular biology is having a renaissance right now, but I don't agree that's due to the number of people working in it. Those advances are largely built on factors that were invented 50 years ago -- breakthroughs in instrumentation (NMR) or technique (PCR), or brilliant insights (Watson-Crick model). The surge of people into the field in the last 20 years is I think a "Gold Rush" like *consequence* of smart people realizing the intellectual endeavors in this field might pay off better than in others, rather than the reverse.
I've been in the business (science research) a long time, and my anecdotal observation (insert the usual caveats) is that advance really is a lot like spectroscopy in quantum world: to go from Here to There, where There is some nontrivial and significant advance, it usually seems a quantum event, someone has to just take one big jump, all at once, and it simply can't be duplicated by any number of people taking any number of small jumps.
There are far more scientific papers published today than were published when I started in the business in the 1980s, but I would be hard-pressed to say that the density of genuinely transformative ideas has increased. We may have essentially hit "saturation" in the sense that throwing more (random) people and money into the process won't get us anything but more chaff, not any more wheat. It's not really the rate-limiting step any more.
What is, though? I don't know. I would vaguely say "getting money/time into the *right* hands -- of people who are capable of genuine breakthrough thinking." Problem is, they're really hard to identify. The guy who invented PCR is basically a surfer bum. There are plenty of people who had one brilliant idea and did zip before and after. It seems deeply serendipitous in many (althought not all) cases. How you improve this I don't know, although you might be able to nibble around the edges by improving the ability of people to just sit around and tinker with "dumb" (by the judgment of committees) ideas, since it's really only ideas considered at the time by the majority to be "dumb" that can turn out (in hindsight) to have been brilliant.
I can think of an avenue that isn't mentioned here but that I'd consider pretty damn important: academia is a horrid place to work at. Researchers have little choice in what they study (and I'd argue that most of the greatest advancements came from people obsessed with their field of study, whose research was guided by interest and their own ideas, not primarily where they'd find an underpaid job). Wages are laughably low. Job security is basically nonexistent unless you get tenure. If driven, intelligent, ambitious people don't get a chance to pursue their ideas, then they likely won't make the breakthrough they are capable of, and very few people really get that chance.
Anecdote: a friend of my mother's defended her thesis while undergoing chemotherapy, and lived apart from her husband and daughter for a decade because their careers were impossible to consolidate in a single city. She's a professor now, but nobody should have to go through that to have a shot at this.
How many people give up on research because of life circumstances? Not wanting to sacrifice their family, or sanity, for meager pay?
Then there's the ruthless pressure to publish, tweak data, the time spent writing grant applications etc, and the incentives that lead to large numbers of basically worthless papers, studies done on twenty college students and the like. Many of the people writing those want to do real research, but can't.
I don't have a solution here, but if we could aim the existing brainpower better (by which I mean, aim it less, because self-aimed talent is always more effective than people forced to work on stuff they're not passionate about) that might lead to more advances than increasing that brain power, or doubling the number of people possessing it.
All this (to the extent it holds) applies to fundamental science. On the margin, would additional researchers have more benefit in fundamental science (which is mostly done in academia) or at applied science (which is mostly done at private companies)?
Somebody wrote that quite some breakthroughs of past centuries were done by English clergy who had comfortable and safe living conditions, good education and enough time on their hands to pursuit whatever they liked. They had no hightech labs of course.
Pre-singularity UBI is probably going to be too diffuse for this; you need concentrations of wealth among smart well-educated wannabe researchers. And it works better if those people can hire lab techs, for which you need people who need jobs (or at least strongly benefit from jobs, which is hard to square with a UBI generous enough to buy lab equipment).
I assume that UBI gives people slack for crowd-funding and institutions, so at least small research projects involving multiple people should happen.
Those English clergy-- did them having real but not onerous day jobs do them any good?
UBI also relates to the argument from Bret Weinstein and Heather Heyer that universities are biased towards expensive research that they can take a cut of, and there isn't enough theoretical work getting funded.
That was a great read, thank you very much, though it doesn't come away saying "everything's fine", rather "It's shit, but it still works, somehow." Life (science), uh, finds a way.
I suspect that there's some overlap with the issue of hiring competent managers. Most bosses suck at bossing - you'd think this is something the market could figure out, but it doesn't. Maybe you could even link it to politicians. The underlying common problem is one of selection of leaders/elites and of effective allocation of limited resources, and market failures seem to be the norm, as well as failures of pretty much every other mechanism we know of. I expect smarter people than me have tried to tackle this, so I have nothing to contribute at this point.
> Selecting for intelligence feels likely to be banned
Quite possibly it will be in some jurisdictions. But if not all jurisdictions ban it, then there are going to be early adopters who want to do it, and once a significant number do, a lot of other people are going to want to, to keep up. There's also the point that if you have the raw data, they can't ban it.
Having said that, +3 IQ points is not a great deal, and for most prospective parents they could get a bigger boost than that with sperm/egg donation. Some people wouldn't want that, but others would.
You say that other people are going to want to select for intelligence to keep up with the others, but how many IVF babies are there going to be to keep up with, realistically? 1-2% of annual US births are IVF, and unless something happens to drastically increase that number, I don't see how adding 3 IQ points to 1-2% of the population (at most) is a compelling reason to unban a practice people consider unethical.
Adding 3 IQ points to the entire population may be easily worth the cost of conceiving every baby through IVF. IVF can have some complications, but they don't seem particularly serious or unsolvable. (You say "unban", but is it currently banned?)
I don't necessarily disagree that conceiving every baby through IVF would be a net positive, but how do you see that happening? I can't imagine how much it would cost to scale up IVF facilities and staff 100-fold, let alone the costs of actually operating them at that scale. Is that really worth the cost? It seems exceedingly unlikely that there aren't better ways to spend that money for the same, or more, benefit.
Things usually cost less, not more, when scaled up. (They might cost more if we are hitting resource limits, but that's unlikely to be a factor for IVF.) Assuming a generous $20,000 for the cost of IVF and genetic selection, it easily pays for itself through the lifetime of the child, even with modest assumptions about the correlation between intelligence and income. And that's not even accounting for the knock-on effects (such as smart people providing greater economic surplus to others in addition to making more money themselves, or a smarter society making better political decisions).
In a world where you can select for intelligence, you can likely select for a number of other health/well being factors as well. Anyone with the financial means to do so would then face pressure to use IVF, and a scale up could realistically happen I think.
That world is a ways away, if it ever arrives, but I don't think its outside the realm of real possibility.
Can we acknowledge somewhere that for all this IVF you need an awful lot of women who could conceive naturally to consent to it? I wouldn’t have put myself through that to raise my kid’s IQ by three points. Maybe if I had a sufficiently horrible disease running in my family, but the assumed chance of various common diseases we do tend to get wouldn’t have prompted me to do IVF just so I could do polygenic screening.
+3 IQ points is a bigger boost in cognitive ability for someone starting from a higher base. I suspect the boost is not uniform -- there are only so many SNPs you can optimize, and smarter folks are already closer to the optimal setting.
But thinking about IQ makes this boost seem zero-sum -- after all, the number itself is relative to the population, not an absolute measure of cognitive ability, i.e., not everyone can "win" in this IQ boosting game. But suppose there was some score for the aggregate effect of those SNPs. Then we'll have an absolute measure for how much headroom we all have (how far do we have before we've optimized all the SNPs?); perhaps all of us, including the smarter ones, are laughably far away from this human ideal. But against this absolute measure (and not a relative measure like IQ is) everyone can (in principle) win, and the ultimate victory condition for the human race is that everyone has maxed out their SNP score, and everyone starts from a level playing field.
If we imagine someone like von Neumann was probably one of the most genetically and environmentally intelligent people, it's conceivable we could all reach around what von Neumann has but due to pleiotropy, I imagine we would start being like him in other ways. I would guess that any living human being is no where near maxing out their PGS for intelligence so we could go well beyond von Neumann, Einstein and so forth. But I think it would take time and have to come at a cost of changes to other aspects of ones being.
>Selecting for intelligence feels likely to be banned
Does not feel likely to me.
The 'don't discriminate against/devalue people with low IQ' argument is something that gets heard a lot by people who fetishize IQ (us), because they represent the natural opponent 'side' to the type of person who would make the argument, and the social media ecosystem is efficient at throwing people into their natural opponents to produce content.
But I don't think any of this is something the average person thinks about, and I think the average person is pretty positive on the idea of IQ=good. I don't think it would occur to enough normal people that this might be something you would want to ban, certainly not enough to result in regulation.
Well in the US maybe. But some other country will allow it and own the world in a generation or two, and everyone in the US will [still] be angry and miserable.
If they're doing the whole thing for $1400, then they're not doing full sequencing on all the embryos (unless there have been some huge breakthroughs which I missed). They're probably using rna microprobes like 23&me does. This means the ability to select for traits they didn't have in mind will be limited.
No, they're certainly not sequencing the entire genome. They're just doing the same old looking for SNP fingerprints. That is presumably why the results are so poor.
Full sequencing is now much cheaper than $1400. Nebula Genomics is doing it right now for $499, Dante Labs runs yearly sales offering it for 300 euros etc., the price has really come down a lot in the last 2-3 years.
It's down to $299 for accurate full-genome sequencing at Nebula. So assuming it's $1400 + $300 per embryo, one cycle of 10 embryos will cost $12k for the basic IVF + $300*10 + $1400 = $16400
It's not linear so it sort of depends on where you are in the distribution. I'm assuming the average IVF-user will be around 115.
Assuming that $1500/year keeps up with inflation, and our discount rate equals the 30 year treasury rate equals the long term average rate of inflation, we can just multiply $1500 by about 40 years of working to get $60,000 as the value of one IQ point.
If instead your discount rate is 4% above inflation (a reasonable forward estimate of the expected return of SPY, which is below historical averages but justified by the abnormally high PE ratio presently) and the income starts 25 years after the IVF, then the value of an IQ point comes down to about $11k, and it's still worth it to get 3 points for $15200.
But assuming the $1500/year only keeps up with inflation is too pessimistic -- it should track overall income growth, which should be 2% faster than inflation. If SPY is 4% above inflation but only 2% above income growth, we use a 2% discount rate on the $1500/year annuity from 2045-2084 to get a present value of $25k.
25k is a lower bound on the value of one IQ point because it only considers the effect on individual income and not any of the other benefits of having higher IQ, such as better health and positive externalities on the community (through better science, better businesses, better political institutions, lower crime).
Getting 3 IQ points with a present value of at least 3x25k for only $16400 is an excellent deal.
The government taxes an average of 29% of people's incomes (https://www.thebalance.com/what-the-average-american-pays-in-taxes-4768594), so from the government's point of view it should be very worth it to pay $16400 now for 29% of $75,000 worth of future earnings. And arguably the government should use a lower discount rate than individuals because its opportunity cost is paying off 30 year treasuries yielding 2% instead of buying SPY yielding 6%. 29% of 3x60k is $52k of present value of future tax revenue that the government could get from paying $16400 for the whole package of IVF and embryo selection. (Before even counting the government's reduced healthcare costs due to the disease screening part).
I think that's probably not the full cost for this purpose.
(disclaimer - I've done some genome sequencing, but only of bacteria.)
The $299 nebula deal is for 30-fold coverage - that's an average, so some regions may be missing. I can't see which sequencing technology they're using, which affects what how much coverage you'd want, and also what sort of artifacts you'd expect to see. All these human sequencing packages only work because there's a good reference, so you might end up with reference sequence replacing a difference they couldn't get a good read of.
That only matters if that region actually differs, and you'll still catch most mutations I imagine. If you care about which alleles are together on the same chromosome, you'd really want to be using a long read technology. Using different chemistries together is good to get better sequences, but I doubt they're doing that.
Don't get me wrong, it's certainly impressive. Given that it's discounted from $1000, it's possible this price is a loss-leader using investor money to build the business, or something. But for the sake of argument, let's suppose not.
However, there's also the issue that an embryo isn't very many cells. You can afford to pinch a few for testing, but for a near-complete sequence you want at least many.
I'm not clear on how much saliva Nebula needs for that service, but it might be ... quite a lot of DNA. I found these statements on the web:
* "The median yield of DNA from a 2 ml saliva sample using Oragene is 110 µg", and
* "How much DNA does a human cell contain? A human cell contains about 6 pg of DNA.", and
* "DNA Sample Submission- Typically 100 to 1000 nanograms of DNA are required for whole genome or whole exome sequencing."
So realistically you probably want to aim for at least something like 200 pg of DNA as an input, or about 33 cells-worth - this ignores all losses in purification.
(You might think that 30 cells would be the minimum /anyway/, if you're getting 30-fold coverage. That's not necessarily the case, but if not it's probably also not complete coverage; you'd be sequencing some molecules multiple times and others none.) Anyway, I imagine these companies are using significantly more starting material than that.
So either you need to grow the cells up, or clone the DNA. Starting with one or two cells, the latter approach would probably give artifacts (missing sections, over-copied sections, sequence changes). If you care very much about the differences, you're going to have to go with the first option - which is going to cost more.
Aren't you assuming the IQ points are a certainty for the cost invested? That is, the investment is risk-free? But biology doesn't work that way. You're investing $15,000 for a certain probability distribution of outcomes with a mean of +3 IQ points. But there is certainly a range of outcomes, and what is the width of that distribution? If it's wide enough it's a pretty risky investment, since the odds are not bad that you get zip for your $$, and don't you need to do some discounting because of the increased risk?
I woudn't think so unless the value of the tails of the distribution is asymmetrical. For early adopters of this technology, I would actually expect it to work in the opposite direction: since the marginal benefit of one additional IQ point is steepest at the tails, and since the average early adopter of IVF is likely to be somewhat above average, the high tail of the distribution is likely to have more positive value than the lower tail, which is closer to average.
To be clear, does a couple doing this with a donor take up additional eggs that could have gone to somebody else, or does it use as many as "traditional" ivf? Neither this post nor the first linked article specified
Generally speaking intended parents will purchase an entire cycle’s worth of eggs from a donor and get the number they get. There are companies that pre-harvest the eggs and sell them one by one but it’s less common.
>Are these tribes based on geography? Are they based on race, ethnic origin, religion, IQ, what TV channels you watched as a kid? I don’t know.
>Some of it is certainly genetic – estimates of the genetic contribution to political association range from 0.4 to 0.6. Heritability of one’s attitudes toward gay rights range from 0.3 to 0.5, which hilariously is a little more heritable than homosexuality itself.
>(for an interesting attempt to break these down into more rigorous concepts like “traditionalism”, “authoritarianism”, and “in-group favoritism” and find the genetic loading for each see here. For an attempt to trace the specific genes involved, which mostly turn out to be NMDA receptors, see here)
I can think of a few governments that might want to select babies for personality, so that citizens are compliant and non-rebellious. And i can think of a few political-moral points of view that might also want to select babies on personality, so as to get future people more likely to agree with their point of view.
The big limiter here is "if you're doing IVF anyway." I doubt anyone would opt for IVF just for the benefit of genetic selection, and I don't think medical providers do the procedure unless natural conception is unsuccessful or inadvisable.
That could happen, but I think it would be many generations away. Unless almost the entire population was screened this way it would take an awful long time for genetic selection to weed this out, assuming people continue to intermarry between classes of non-IVF/IVF born humans.
Maybe far in the future, after all genetic risk factors are removed from the gene pool. But it seems unlikely to me that we'd abandon this practice after using it extensively enough to eliminate genetic risk factors, because:
1. There are always random chromosomal mutations that you might want to screen for.
2. If we get accustomed to "picking the best embryo", then we might get used to all the benefits to be had from selecting the best combination of the parents' genes, rather than just removing any actively-bad genetic risk factors. (Selecting for the highest-IQ combination being one obvious example.)
The marginal benefit is very small compared to intentionally selecting a mate for good genetics, or if you have a history of disease in your own family, not breeding at all.
Other complicating factor is the marginal benefit depends on where you sit on the margin. If you have very healthy genes already, you get a lot less out of this than someone who doesn't.
And, obviously, if you're not a woman, this isn't your choice anyway.
after some point this process will go from obscure to mainstream, and then it will be something parents desperately want to do, along the lines of getting accepted to the best pre-K daycare and enrolling kids in college-prep classes in middle school.
I would. There is an history of mental illness in my family. If IVF is the only way to seriously reduce risk, I'll go with it. The current plan is to not have any, since I don't wish the hell that can be on my children. I get why people would think that weird but I would be unable to look at my child face if there were any way to avoid a depressing disability that I didn't do.
My wife's brother is an institutionalized schizophrenic. If this had been a reasonable option when we were having our kids, I would have gone for it 10 out of 10 times. Schizophrenia is scary as hell.
How exactly is this "relative risk reduction" measured ? They say it is "extrapolated from empirical data", but I don't know what that means.
If they mean, "we implanted N embryos, half screened using our algorithm and half at random, and the screened ones had X% less prevalence of genetic diseases in real life", then I might be mildly interested. On the other hand, if they mean, "we obtained a bunch of markers from GWAS, screened all the embryos for them, and assigned a score to each embryo based on its alleles", then I'm almost completely uninterested, because human traits (outside of a few outliers) are so polygenic that you can basically calculate whatever result you want based on how you tweak your model parameters.
One way to verify it would be the following: You sequence the genome of many pairs of siblings where one got some disease and the other didn't. You use the data from only half of the pairs to construct your algorithm. Then you apply the algorithm to the other half of the pairs, and look at how often it would have picked the one who didn't get the disease.
I don't know what they actually did. It's certainly not "we implanted N embryos, half screened using our algorithm and half at random, and the screened ones had X% less prevalence of genetic diseases in real life", because that would require them to actually implant the embryos decades ago.
Yes, I understand that you're talking about training your model and then cross-validating it. The predictive value of such a process is not zero, by any means; still, based on what I've seen from GWAS before, I doubt its effectiveness in practice.
Unfortunately, we can't possibly know if this works until many more polygenically screen babies are born, then wait 70 years to see if they really live full lives with lower rates of the indicated diseases than regular babies born to the same parents. That will likely never be possible because parents won't randomly select only some babies for screening, so we'll be left with the next best comparison to babies from other parents.
As I described in the sibling comment, and Steve Hsu has also described below, we *can* possibly know if it works by sequencing the genome of pairs of siblings who are now old, and looking at whether the method would have picked the healthier one.
You can possibly know if polygenic screening in general could work. I'm saying you can only know if one specific company's product works by actually testing the results of that product.
Time to start campaigning to get lots of IVF parents to have two kids, do polygenic screening on both, but then the lab randomly selects one of the two to ignore the parents' selection and pick an embryo at random instead (this is the control group)
Think of the targeted advertising though!!! And the intricate legal arguments for like the inclusion of a kibra variant that gives you near eidetic memory but also makes it that much easier to develop PTSD
Although given how easy it is to use patented technology that's technically different but functionally/biologically not because law is so far behind on understanding biology, I'm sure the parents won't win? On the other hand Erin Brokovich sometimes happens when irl she would have had an actual scientific case doing like neuroblastoma rates in Rockford Illinois where furniture manufacturing first took off
I am thinking that now, and thanking God (or rationalist equivalent higher power) we already have 3 passably functional kids and not in the market for any more 😉
The entertainment value is diluted for me by imagining the way parents will treat children who are so disappointing. There's enough abuse already without adding genetic engineering to the mix.
Is there a genetic basis for being emotionally abusive? Would anyone sign up for it being edited out of their children?
I'm sure that the companies will be very careful not to promise too much, for exactly this reason. I doubt you can sue them if you get cancer or a rare genetic disease, for example.
B. Even a very bright designer baby, apparently capable of reading weeks after birth, won't have lived long enough to understand that those labels correspond to extremely low absolute risks.
Poor baby probably thinks all babies are killed by consumer products by the age of 2.
I saw a search result that stated that 'dawn' is _one_ of the meanings of 'aurea' and results with other unrelated meanings as well, so I'm not so sure that 'aurea' as 'dawn' is definitely wrong, especially given both the way language works in general and that there are lots of languages (and dialects) based on the supposed origin language of the term (Latin).
And 'golden dawn' is a pretty common phrase too, 'aurea' seems (based on my cursory skim of search results for "aurea") based on Aurora anyways (which was the goddess of the dawn), so ... I'll give Scott a pass on this 'mistake'!
The adjective 'aureus' means something closer to 'the light of day,' which itself is golden - alternatively, it could mean something like shining, excellent, etc. (the etymology being derived from 'aurum')
Dawn, as in the morning/daybreak, is always aurora. It gets confusing when you factor in the unrelated 'aura -ae,' since this has a Virgilian connection with the heavens and daylight, versus the darkness of the underworld.
I am concerned that we do not understand this well enough. What if, for instance, we find that genes that correlate with disease also correlate with some particular emotion? Or that (the genes we believe increase) intelligence are inversely correlated with empathy? Under a host of horrific hypotheticals, widespread adoption could be catastrophic, creating an entire generation that is missing an attribute, has far different statistical outcomes from the norm, etc. I leave it to those with more imagination than myself to generate better scenarios, and those with more knowledge to figure out if they could actually happen.
This makes Heinlein's Methuselah Project look like it belongs in a high school science fair. This is strong medicine. It will be applied exclusively by the ignorant (since that's all of us, right now) and, also, mostly by idiots who haven't thought about what they are doing.
I strongly suspect it will be done, at least in some if not many places, and I believe the impact will be large. I do not know if it will be positive or negative - or, more likely, both.
"For He knows what we are made of, and that it is dust." But perhaps not for much longer.
Chin up. Biochemistry is so unbelievably stuffed with redundancy it seems very unlikely to me to be anything more impactful than the cloning of Dolly the sheep, which was going to usher in a Brave New World of cloning in about 8 months flat, 25 years ago now. If it were *possible* to routinely pick out 1 out of 10 IVF embryos that would end up very different from its parents -- 2x smarter, wholly free of disease, able to leap buildings in a single bound -- then this kind of thing would happen out in the wild in 10% of natural births already -- and that is not what we see. Children generally end up pretty similar to their parents, and wild deviations, where a genius is born from IQ 105 parents, say, are exceedingly rare, 1 out of 10 million kind of events. So yeah if you could screen 10 million embryos, you might pick out the one rara avis and get results that would make the Howard Foundation proud.
It's literally just embryo selection. Genetic counselors have been informally doing this for a while. They're not interfering or engineering in any way- like editing blastocysts with strong promoters around magic machiavellian genes to ensure psycho hitler.
Like we are literally closer to Jurassic Park being a reality than your vision of human genetics - https://pleistocenepark.ru
- the literal Adolf Hitler was conceived naturally
- psychopaths are conceived naturally every day
- a small percentage of people are willing to defy norms and start respectability cascades
It is possible to set everything on fire with only quantitative changes.
That said, there are some obvious bounds here. If a trait has frequency X0 in the population, this form of selection is taken up at frequency Y, and the average number of embryos selected from is Z, then the frequency of the trait X1 after one generation is bounded by:
Yeah, this is right. In particular (1) I bet those graphs reflect prediction from pooled population samples, not causality estimated from sibling groups and leveraging the "lottery of meiosis". In which case, embryo selection may be less effective than predicted, maybe even have zero effect in some cases. But also (2) we have no idea what all these genes actually do, we've got no idea about the biological pathways between them and the outcome, we've got no idea of possible side effects. Basically, this might be about as irresponsible as handing out an untested drug.
Fortunately IVF is extremely expensive and unpleasant, so we'll have a very small number of test cases to look at long before the technology becoming ubiquitous is an option.
If there's some innate problems with these techniques, we'll have a chance to see it before it affects the general population, and adjust.
This is a valid concern. It is possible that if we selected strongly enough for trait X, it could decrease (or increase for that matter) trait Y in a way we don't like.
But there are three reasons I don't think this is going to be much of a problem in the next 50 years.
1) The strongest negative correlation between two disease traits we know of is the correlation of kidney disease and ulcerative collitis, at -0.3. Most traits seem to be mostly independent of one another.
2) We don't have that much selective power right now. There are two limiting factors for embryo selection: the number of embryos you have to work with and the percentage of variance in the trait that you can explain with genetic testing. Even with a really good genetic test (which we don't really have right now), and a lot of embryos (like 30 if you start egg freezing early), you'd still only be able to get about +/-1 standard deviation on any given trait.
3) We can largely mitigate this possibility by selecing on multiple traits. If we're worried that selecting against lung cancer risk may accidentally select for genes that make you die before you can develop lung cancer we can introduce a test for healthy lifespan.
4) There are many tradeoffs that humans made in their evolutionary past that are clearly not well selected for the modern world. For example, humans have very short lifespans given their low rates of all-cause mortality. If there is a gene that makes you likely to reproduce younger but kills you at an old age, that gene will be selected for in environments with high all-cause mortality. If you are likely to die anyways from some random unavoidable cause, evolution would much rather you reproduce before then. Modern humans have something like 1/10th the death rate of hunter-gatherers at ages before 50. So even if we're doing what evolution does and optimizing for inclusive reproductive fitness, we STILL would have a lot of fertile ground to explore just by taking the obvious steps to decrease disease rates.
Re 1) - there is a stronger negative correlation; congenital total blindness + schizophrenia has never been found. Of course, essentially everyone would pick "possibility of schizophrenia" over "blind", so this is not really a notable tradeoff.
Re 3) - there are a couple of sticky cases. One is where legible trait A is correlated in a tradeoff with illegible trait B, but because B is illegible you don't (yet) know about the correlation. The other is the "mean chickens" problem: some of the obvious criteria to optimise on, like income, may actually optimise for greed rather than productivity (like how "hen in the shed with the highest egg production" optimises for the hen that pecks the other hens to make them too sick to lay, or "beetle group with the lowest population" optimises for beetles that breed like crazy but then eat *other* beetles' babies, or how democracy optimises for demagoguery more strongly than it optimises for good governance, or how Enron's attempt to use evolution by firing the "least productive 10%" of workers optimised for cheating on the metrics).
Interesting point about schizophrenia and blindness. I didn't know. My comment was based on data from LDHub, but I guess they don't track schizophrenia + blindness?
You're right about the issue with illegible traits of course. I think that is one of the biggest potential risks with embryo selection (though I don't think it is likely to become an issue until we start to push substantially beyond the tails of traits in existing humans). Evolution deals with this issue by trying everything all the time and letting its mistakes kill or cripple organisms. It's a pretty brutal system, but it "works" in the sense that it generally leads to fitter species over time.
But I don't think such a brutal system is actually necessary. Evolution is in some sense the dumbest possible algorithm for creating complex systems. The miracle is not that it works so well, but that it works at all.
Somewhat skeptical of the efficacy of all this when most of the data comes from the company itself. How strictly is something like this regulated? Is there any way to verify that when they for example that there's a 60% lower chance of cancer that the math they're using adds up?
> Is there any way to verify that when they for example that there's a 60% lower chance of cancer that the math they're using adds up?
Yes. None of these companies are big enough to fund their own genetics studies yet, so all the predictors come from open-source databases like this one: https://www.ebi.ac.uk/gwas/home
Furthermore, most of them public their predictors in articles you can find on SciHub, so you can see the set of SNPs they use to contruct the predictors. It might be hard to replicate their findings yourself, but there are very often studies from unaffiliated scientists that have predictors capable of explaining a similar level of variance.
The math to calculate expected reduction given parental polygenic risk scores, number of embryos and disease prevalence is not controversial. It's pretty standard order statistics on normal distributions. The only real question is what percentage of variance their predictors can explain, which is where seeing that other researchers have constructed predictors with similar levels of explanatory power is reassuring (or not, depending on what you find).
On one hand the article seems to suggest that this technology is not very effective. On the other hand it expresses concerns about exacerbating inequalities. I feel like at most one of these two concerns can be valid; not both at the same time.
There is a section "unintended consequences" which says that selecting for high IQ would also increase the risk of bipolar disorder. What's not mentioned is that selecting for high IQ would decrease the risk of most other diseases. Bipolar disorder is an exception in that regard. Genetically, most good things cluster together with other good things. So most unintended consequences would actually be positive.
It's worth keeping in mind that most scientists have career goals in mind, and that an article endorsing these technologies might currently not advance these goals as much as an article which is critical of them.
David Plotz wrote a book about the much derided Nobel Prize sperm bank in 2005 by interviewing the children. He was impressed by the offspring, who struck him as on average intelligent and thoughtful (at least the ones who felt like engaging with the man from Slate).
On the other hand, with well over a million children in the US having been conceived via sperm or egg donations, I've never noticed any large scale social effects from the purchasing of selected gametes.
For example, I presume that lesbians, as in the movie "The Kids Are Alright," are much more likely than heterosexuals to have children whose biological fathers were selected from sperm bank catalogs. Do lesbians therefore tend to have super children? I don't know. I've never heard that they do, but maybe they do. Has anybody ever heard of a study?
I used to follow whom lesbian celebrities used as their sperm donors: generally, other celebrities.
A sad story: Back in ~2000 I thought it unwise of singer Melissa Etheridge to use noted substance abuser CSN&Y singer David Crosby as a sperm donor even though he'd just gotten a liver transplant.
Granted, "it seems likely to me" is a weak statement, but it seems likely to me things like selecting donors from sperm banks and even polygenic screening can't make much of a difference compared to existing assortative mating practices. The women for whom having that kind of choice might matter can't afford it anyway. You're left with some tiny segment of women sufficiently affluent and living in the right place, but somehow extremely unattractive anyway.
Which is to say the hetero women in the same social class as the lesbians taking their pick from sperm banks are just marrying the sperm bank donors.
Something interesting to see would be adoption of practices like this to breed super-athletes, though. Given how common lesbians are in the ranks of extremely elite female athletes, we're arguably missing out on being able to do things like breed Kobe Bryant with Diana Taurasi. Taurasi never did reveal who her donor actually was.
My impression is that lesbians can also choose to get sperm from a male friend. That would involve fewer options, but is cheaper. I would also assume they'd chose a friend who doesn't have obvious genetic problems.
This would obfuscate whatever effects there are from IVF.
Here's some background on the validation of polygenic risk scores, pleiotropy, etc.
The effectiveness of polygenic disease risk predictors is tested using tens of thousands of siblings for whom we have genotypes and medical history (they are typically 50-70 years old). We specifically test how well the predictor can pick out a sibling with the condition from a pair:
"Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc."
Risk reduction has been validated using sib data in several independent studies.
Sibling validation of polygenic risk scores and complex trait prediction
We test 26 polygenic predictors using tens of thousands of genetic siblings from the UK Biobank (UKB), for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in between-sibling designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. 55–65% of the time the higher PRS sibling is the case. For quantitative traits such as height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.
See also this 2021 review article, to appear in "Genomic Prediction of Complex Traits", Springer Nature book series "Methods in Molecular Biology"
Among other things it discusses pleiotropy and the genetic architecture of disease risks. DNA regions used to predict different risks are largely disjoint. Selection on a risk index (e.g., 10 conditions) has been shown (using sib data) to deliver average risk reduction for all of the diseases in the index.
What is known about the long-term health effects of IVF? My understanding is that people born through IVF are pretty normal as far as we can tell, but the oldest person born through IVF is now 42 so there are possible long-term effects for which we just can't tell. I want to point out the risk that if IVF embryo selection becomes really effective people will start using IVF when not medically necessary, and will eventually suffer long-term health effects that we aren't aware of because nobody with IVF lived that long yet. This risk seems pretty low, though.
You don’t need to reach for unknown long term effects. There’s a statistically significant increase in birth defects.
I don’t think even LifeView would say the benefits outweigh the risks at the present time if polygenetic scoring is the only reason you are considering IVF.
"There’s a statistically significant increase in birth defects."
Is this before or after after controlling for the age of the parents and all their other preexisting conditions? Age and other prexisting conditions would increase both birth defects and the infertility that causes people to seek IVF in the first place.
There’s a debate in the literature. After familiarizing myself with it I was convinced that the effect size is reduced but still exists. Your conclusions may vary.
this sort of thing is probably genetically confounded, because genetics would contribute to the fertility problems that caused their parents to seek IVF.
I would love to see an RCT where a few hundred young healthy fertile couples pre-register and half of them are randomly selected to get IVF with embryo selection.
There are lots of problems with IVF. In natural conception, all the sperm compete to overcome the female fortress of the birth canal to get to the egg. Only one wins. This is a profoundly powerful method of natural selection of the fittest. In IVF, there is no natural competition for the egg. All the sperm are mixed with the egg, and the lucky one wins. This selects for the middle of the probability distribution, i.e. for the average sperm.
Using polygenic scores for IVF starts with an average embryo and then hopes to increase the probability for a marginally higher than average embryo. If IVF were done on a large scale it would have a regressive effect on the human population. See this video by Ed Dutton:
Admittingly this kind of concerns me. Some of our most brilliant people have been clinically flawed in some way (like John Nash, Elon Musk Nicola Tesla) and there's good reason speculate that their "bad genes" correlate with or are the cause of their brilliance. Who knows what geniuses we would be depriving ourselves of?
I actually think they get a pass on outright eugenics with that; sounds more like supercharged selective mating. Not free of problems itself; but; I don't see a slippery slope down from there aside from perhaps single women choosing to do the same rather than settle for someone they feel is beneath them. But, even if everyone did that; you're at worst condemning nearly everyone to live romantically empty lives and preventing 99% of men from reproducing but allowing free competition for those 1% slots; the worst case scenario doesn't involve anyone having to die; though violence rates would likely shoot up amongst men without wives and children to mellow us down, and in that hyper competitive environment. (Ref Johnathan Gotschall's "The Professor in the Cage")
Whereas this polygenic screening if adopted by everyone, results in billions of unique human beings being created, tested, and snuffed out immediately if not found to be the best amongst their dozen or so siblings. And by setting the standard that, having say, Down Syndrome, is certainly reason enough to not bring someone into the world, you make it so very easy to discard the lives of people who are born with Down Syndrome. Imagine a world where "He should have been screened out, but his parents conceived him irresponsibly and didn't get him tested and terminated." was a common reaction to people born with such diseases?
One of these is a far darker outcome. The lesbians can have their sperm bank catalogues; even if I'm never going to reproduce in that world.
No, most people don't think that if it's OK to screen out a disease before birth (or even before conception), then it's OK to kill a person with that disease after being born. Down syndrome is already easily screened out in prenatal testing, but we don't go around killing people with Down syndrome.
>I don't see a slippery slope down from there aside from perhaps single women choosing to do the same rather than settle for someone they feel is beneath them.
If a man has zero hope of ever getting someone to bear his child consensually (you say 99%), and values leaving offspring above everything else (not a majority, but non-negligible - say 1%), "rape a woman and kidnap her for 9 months so she can't abort" is his highest-utility option. Success rate and penalty are irrelevant, because E(offspring) dominates the calculus and E(offspring|don't do it) = 0.
This is probably not a great thing to incentivise.
True, but here it's a specific perverse incentive rather than the fuzzier general effects of bachelorhood. This scenario is also dire enough that I feel it merits being laid out in full.
> And by setting the standard that, having say, Down Syndrome, is certainly reason enough to not bring someone into the world, you make it so very easy to discard the lives of people who are born with Down Syndrome.
I really don't see how that follows. You're effectively arguing that accepting the legitimacy of abortion "makes it so very easy" to kill babies after they're born if you suddenly change your mind on raising a child. There are so many propositions you'd have to justify to go from one to the otherand you just gloss over them as if they're immaterial. There are plenty of opportunities to make relevant distinctions that would permit one outcome but not the other.
I mean, Ian is actually positing the more ambitious "it will make Aktion T4 seem more attractive" rather than "abortion and infanticide are not so different", but I'm going to have to go in to defend the latter as legitimate.
There are exactly two propositions dividing abortion from infanticide - bodily autonomy (which stops being a justification at birth, but which is largely a fig leaf for reproductive freedom anyway) and threshold of full killing-is-murder personhood (which has to be after birth for infanticide, while it merely has to be after [stage of abortion] for abortion).
There are a *lot* of historical societies that practiced infanticide-by-exposure as a means of population control (and - well, not quite eu*gen*ics, but eu*phen*ics; preventing disability). It is not something foreign to humanity.
Of course, I'm one of the people in the Singerian camp on this i.e. "thus infanticide isn't terrible" as opposed to "thus abortion is terrible". But there really isn't as much of a distinction as you make out.
> I mean, Ian is actually positing the more ambitious "it will make Aktion T4 seem more attractive" rather than "abortion and infanticide are not so different"
That's my point though. Since we don't accept the less ambitious proposition for various meaningful reasons, it's absurd to think that we would accept the more ambitious one and that there are no meaningful distinctions to be found there.
There’s no editing. The IVF process already produces multiple viable embryos (or at least those going through it hope so). This is just a way of deciding which one to use.
The article says 'the test is fully named “preimplantation genetic testing for polygenic disorders”, or PGT-P for short.' I was also thinking something something pre-implantation something
I'd prefer that article balance the Down's-mother interviews with interviews with the Down's patients themselves - including the ones who have outlived their loving parents. It's possible Down's is a net happiness gain, at least in a rich society, but this deserves a good deal of skepticism.
Yeah, seems more like a "Hey, here's a silver lining I'm going to focus on." which is probably a fairly healthy way of dealing with things.
But on the balance, if we could cure people with down syndrome, it would probably be better in general. But eliminating people with down syndrome before they're born does not equal curing it in people. And living with down syndrome is a lot better than not living.
it's pretty similar, because in this case "eliminating people with down syndrome before they're born" results in a healthy person being born instead (a healthy embryo is picked instead.) So as far as consequentialist outcome is concerned, it's the same as curing it.
This is messed up on multiple levels. Besides the obvious ethical considerations of having an entire social system based around meritocracy being gamed by innately increasing merit potential and essentially playing God based on unclear and short sighted principles, this is something exclusively available to very wealthy people having children very late in life. At a base it would accelerate wealth inequality and the entitled position that many silicon valley and finance bros have in regard to virtually every other segment of American society. Must be stopped at all costs.
> this is something exclusively available to very wealthy people having children very late in life
No, it isn't. IVF itself costs something like $10,000–15,000, and genetic selection is a couple thousand on top of that.
> At a base it would accelerate wealth inequality and the entitled position that many silicon valley and finance bros have in regard to virtually every other segment of American society.
Inequality isn't a problem in and of itself. Poverty is a problem. If inequality increases because the poor are getting poorer, that's a problem. If inequality increases because the rich are getting richer, that's not a problem. Preventing an increase in inequality by banning a procedure that would help the rich get richer but wouldn't make the poor any poorer is terrible tyranny.
I used to feel this way (re: inequality), but it does seem that as a social species (dogs, monkeys, humans, etc.), inequality is itself sufficient to cause social strife. Poor people in the U.S.A. and Western Europe live better than 99% of people historically -- there is almost no real hunger (rather the opposite), there is increasingly a right to shelter, free medical care that, while relatively bad, still far exceeds what anyone had access to pre-modern-medicine.
Additionally, Blacks in the U.S.A. do better than their ethnic peers in sub-saharan Africa; Hispanics than their ethnic peers in South America, etc., but there is still enormous dissatisfaction with inequality.
Conversely, that the chief of some hunter-gatherer tribe -- who has lost 2 of their 6 children during childbirth, who has no expectation of living in their frail elderly years when they cannot walk, is probably quite happy.
Also, in the more reasonable variants of discontent about inequality, people are angry that the wealth of the rich isn't being redistributed to the poor (or, rather, not more of it than currently is). Now, it's questionable if demands to redistribute more wealth are legitimate, or if it can be redistributed without shrinking the pie too much. Nevertheless, the demand is for a policy that would make the rich less rich in a way that at least potentially benefits the poor.
However, keeping the rich from becoming smarter makes the rich less rich in a way that doesn't help the poor in any way. If anything, it reduces the amount of wealth that can be redistributed to the poor.
I generally agree about "The rich getting richer isn't a problem" if "the poor aren't getting poorer" but it does become a problem in at least a couple of areas, most obviously; land. If the rich keep getting richer while the poor stagnate, land prices will rise as the rich compete with each other and the poor become priced out of the land market.
Which is what is happening in North America right now, leading to many people renting and paying money to wealthy landlords instead of owning a property that they can invest their time and labour into.
Hispanic poverty doesn't seem to be nearly the political issue that black poverty is. Presumably their choice to move to the US for a better life is a big part of that.
10,000 to 15,000 expense literally eliminates at least 75% of the country from affording this. IVF is also more like 40-50k nowadays. This is like half of the median take home income of the average American household. America is not SF and NYC. That procedure is effectively considered genocide by like more than half the religious groups in the US.
Half of the *yearly* take home income, or perhaps 1.2% of the lifetime income, for a procedure that (depending on the attributes selected for) may benefit the child for a lifetime. Sure, many people are unwilling to save up a few tens of thousands over a few years, but that doesn't mean that no one but rich people are *able* do it (let alone, as you said, "exclusively very wealthy people", which to me sounds like much less than the top 25%).
Like there are virtually zero banks that will underwrite this loan and at average US savings rates you would be in your late 40s assuming you got married in your mid-20s to afford IVF.
That the average American saves little and has $700 of savings doesn't mean that the average American wouldn't be *able* to save more if they wanted, and have much more savings.
I'm not, as you've insinuated, a rich person from SF or NY. I'm from Hungary, a country where typical salaries are well below those in America, even adjusted for prices. Most Americans, if they were just a little thrifty, should be able to save a large fraction of their salaries.
Well, richer than... most of Africa, the Middle East, India, and Southeast Asia.
Oh, and let's not mention the amount of people who would be categorically opposed to such things due to religious reasons (i.e. the majority of the world).
> Inequality isn't a problem in and of itself. Poverty is a problem.
That's speculative. If human wellness is somewhat predicated on comparative wealth, as it appears to be in some cultures, then large disparities in equality *is* itself a problem.
Stopping human improvement at all costs seems like an extreme position.
Yes, it will almost certainly help the wealthy over the poor. This is true of every human innovation in history, basically. But as with many other innovations, it will likely drift downward to help the poor at some point, especially as society starts to understand that increasing the potential of every citizen is likely to make the whole country/world better off, not just the lives of those who receive the intervention.
There would almost certainly be an intermediate period where inequality rises in some ways, and this could lead to social strife, but I'm confident at least some more conscientious countries would eventually make something like this available to lower classes as it becomes a human rights issue of sorts.
It would also become something of a competitive aspect of foreign affairs. If (insert foreign adversary here) is providing genetic selection to their population, there will be pressure on you to do so also, as they are improving their citizens natural abilities and could outcompete you in industry/military/whatever.
It's definitely adjacent to it, no question. I wouldn't deny that. But that doesn't mean the idea has no merit at all. It just means we need to think very carefully about what we are doing, why we are doing it, and how, and yes, try to make it as equitable as we can. In my ideal world we remove wealth from the equation entirely, but in our current system that just isn't a possiblity.
It could all end up horribly I suppose, hijacked by racist/prejudiced powers, but it also seems like potentially the best avenue for transcending our current limitations as a species, which are many. The risk vs reward on all of this is unclear, and I could see how many could have a worldview where the risk is too substantial to even contemplate the idea.
But taken on its own as a concept (while granting that removing many things from sociological context makes them appear more attractive), I don't believe there's so much that is objectionable to the idea of improving the odds of an unborn person being more intelligent/kind/whatever trait you could imagine as a societal/individual positive.
I'm all in favor of taking anything like this slowly, with great deliberate thought, and listening to every objection and taking them seriously. Maybe in the end it will be clear that we shouldn't do it, or place extremely restrictive regulation on the entire practice. But to squash it out of fear that it could be exploited without a hard examination of the possible benefits doesn't strike me as the way to go either.
Yeah I'm left with the sense that even if we had tens of generations of strife around this, the next thousand generations would benefit so much that the downsides are trivial
I feel like this is a reductio ad Hitlerum; Nazi eugenics were bad because a) they sucked at race science, b) their eugenics involved mass murder.
This is not a risk-free or drawback-free path to take, but "same plan, but skip the step where you murder ten million people" is actually a rather substantial improvement!
I really think that this is the most promising way to end poverty, inequality, and various social ills, and that banning it would doom billions to terrible lives. And that's even before we get to the civilization-wide benefits like having smart people cure cancer, discover limitless green energy, etc.
Really smart people invented atom bombs and centralized agricultural collectivization and logistics networks to move millions of people to death camps. Really smart people often are just more effective at doing evil than normal people or dumb people and can obfuscate it through several levels of social hierarchy. Intelligence is a good indicator for things like income and social status, but not being a good person, a compassionate person, a caring person, or even a reasonable person. I know plenty of smart people that have reached the heights of their current system who are also insane political extremists who will put their opponents in camps at the first opportunity (on both sides). This is even assuming that the connection between IQ is even that strongly correlated with good outcomes besides the possibility for a bajillion other cofounders.
This is also assuming that we have the complex system that is genetics so thoroughly mapped out that we are not just creating a bunch of Ubermensch like Khan from Star Trek who are really smart and complete sociopathic.
This falls into the neoliberal trap of arguing that there is no need to fix the system, just to enable a purer meritocracy that still maintains all of the trappings of the current system. The most promising route to a better future is just not treating people we consider our economic and social inferiors like shit.
I have three questions someone who is familiar can help me with hopefully.
>There are two ways that an egg may be fertilized by IVF: traditional and ICSI. In traditional IVF, 50,000 or more swimming sperm are placed next to the egg in a laboratory dish. Fertilization occurs when one of the sperm enters into the cytoplasm of the egg. In the ICSI process, a tiny needle, called a micropipette, is used to inject a single sperm into the center of the egg. With either traditional IVF or ICSI, once fertilization occurs, the fertilized egg (now called an embryo) grows in a laboratory for 1 to 5 days before it is transferred to the woman’s uterus (womb).[https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/what-is-intracytoplasmic-sperm-injection-icsi/]
1. What effect does directly injecting the sperm have? I assume that swimming to reach the egg and penetrate is a test of fitness. But how much does it matter?
2. If there is a substantial negative effect to directly injecting, would making more and more sperm go through an extremely difficult process before fertilizing select for a healthy sperm that would help make a healthy baby?
3. After enough generations of ICSI, do sperm stop swimming enough to get a woman pregnant? Does IVF cause the need for more IVF?
My wife and I went through a couple of cycles of IVF recently, and actually chatted with Genomic Predictions (the name of Prof Hsu's company beofre it changed to LifeView apparently). For us the big challenge was that the fertility clinic we used to harvest the eggs and then implant the embryo was very limiting in what they would allow us to do in terms of selecting embryos. We were already testing for a (mild) genetic defect I have, and their policy was that if any embryo tested positive for it they would refuse to implant it, in spite of the mild expected impact. (On the other hand if we didn't test for the condition they would accept the 50/50 chance an embryo had it and implant any of our embryos.). When we raised the idea of using something like polygenic risk scoring they shut us down immediately. This is a well known clinic affiliated with a top US hospital, but I looked around a bit and got the sense that it would be a struggle to find a clinic (in the US) that would accept this kind of embryo selection process, although the fact that a baby was born using it suggests maybe this wasn't as much of a challenge as I thought. The solution I considered was finding the egg donor in the US and using our normal clinic to harvest the eggs and create the embryos, then having the genetic testing done, then transferring the embryos to an international clinic more willing to allow us to select the embryo using whatever criteria we wanted.
I guess I'm outing myself as a religious conservative, but you wouldn't have to be a religious conservative to see those embryos that don't get chosen with something like compassion.
Granted, an embryo does not suffer, so the unchosen embryo will not know it never even had a chance. And also granted that many embryos don't survive to birth anyway.
I'm a father of five. One of my daughters is autistic, not too severe, but enough that she'll likely not be able to live independently. I am grateful every day that she's part of the world. My youngest child had markers for Down syndrome while my wife was pregnant with him. While we would have loved and cared for him either way, we were grateful that this turned out to be a false alarm. I like children, and would have wanted more, but five kids is already a lot, so you make your choice.
I'm not sure what my point is, but it's something like this: if life is good (and I think it is), then even a life with some pain or sickness may be a life worth having. I guess I'd like to see some sort of organization established to take all these unchosen embryos, and, at some future date, give them a life and a home somewhere. If my vision of the future is right, I could see many happy, not-quite-perfect children growing up in big, beautiful O'Neill cylinders in the sky.
It is true that all these embtyos are potential lifes that never are, but so is every period a woman has. Are you also founding a center to save them as well? it seems like the value you are trying to maximise for is the amount of happy lifes, however the people doing these tests were always only going to have one child (at least for now) anyway, so this technology makes no difference there.
They are not potential lives: they are lives. I believe you meant to say they are potential people, but to say they are potential lives is scientifically innacurate. The zygote is the first stage of human life, biologically speaking. An egg, as you point out, is a potential life, in that it has the potential to become a human life if it is fertilized. A zygote already is a life, regardless of whether you think it is a life with moral value.
If I told you i have saved 7 lives this week you would feel really impressed until you discover it were those of the floers of my neighbor that weren't getting any water. You would be justified in feeling like you were lied to. Specifically because the context indicated taht i was probably using the definition of life that refered to that of a person or a moral agent. I was using that definition above as well.
Your comment said that an embryo was a potential life in the same way "every period a woman has" and then asked "Are you also founding a center to save them as well?" Which is a false equivalence that I took umbrage at. It's much more reasonable for someone to feel they have a moral responsibility to an actual human life as opposed to a potential human life.
Late to the discussion, but I wanted to weigh in with this thought. We are coming close to the ability to reliably induce totipotency in previously differentiated cells. What is the line for you in that world? What level of intervention is required to ensure every shed human cell is given the opportunity to develop into a full human being?
This is a misunderstanding of my point: I'm trying to differentiate between potential human lives, and actual human lives from a biological standpoint. A zygote is the earliest stage of human development: it is a human life, not a potential human life. An egg is a potential human life because it has the potential to become a human life under certain circumstances (being fertilized). Human cells generally do not have the potential to become a human life and thus are not potential human lives. If we do develop the ability to induce totipotency in differentiated cells then all that changes is the types of cells which are potential human lives. A skin cell currently cannot become a human life, and thus is not a potential human life: once we have totipotency technology it could become a human life under the right conditions (someone intervening to make it totipotent in such a way as to become a new human life). It thus raises the status of skin cells to be equal to egg cells, not equal to zygotes.
So your line is if the development into a fully grown human can happen naturally or requires technological intervention? But I fail to see how this meaningfully differentiates between an embryo in a petri dish and a somatic cell in the same dish that is one experiment away from totipotency. The two cells have (roughly) the same contents, the same DNA, and only are fundamentally distinguished by which transcription factors are bound to which genes at that moment. I'm oversimplifying to be fair, but it still seems like a rather arbitrary line to me.
It's not my line: it's the biological line. Human life begins with the zygote: that is the earliest stage of biological development for a human. It doesn't begin with an egg, or with a sperm, or with a skin cell, it begins with a zygote. This isn't controversial (see https://en.wikipedia.org/wiki/Development_of_the_human_body , or https://bio.libretexts.org/Bookshelves/Human_Biology/Book%3A_Human_Biology_(Wakim_and_Grewal)/23%3A_Human_Growth_and_Development). A fertilized egg is a human life: a human life at the earliest stage of development, but a human life nonetheless. Presumably if you could induce totipotentality into a human cell then you would in effect be creating a zygote without the use of an egg, but it doesn't change the fact that you would have just created a new human life that is now at it's earliest stage of development.
I'm not here to argue about whether zygotes have rights, I'm here to be a pedant who doesn't like it when people confuse potential human life with actual human life in their arguments. If you have a problem with my definition then take it up with the biologists.
Unlike embryos, periods are not human lives. What would "saving periods" even mean? It's nonsensical.
Periods don't even coincide with either ovulation or the creation of embryos. Periods happen about two weeks after ovulation, and typically only if there is no embryo to nourish.
If your parents did anything different at all the night you were conceived you wouldn't exist. But someone else most likely would! There were 100 million sperm so even the tiniest change and another one would have made it to the egg first. And someone else would exist and you would not.
An embryo outside the body can't develop unless someone makes a choice. So, to me, they aren't really that different from a sperm and an egg. Just like you exist because your parents decided to get it on at that exact millisecond, so two those embryos can't exist unless someone decides to implant them.
I mean....they do exist though. They cant develop unless someone decides to implant them, but they were created and by your own choice. I can understand why someone would feel some responsibility for life that they created through their own deliberate choice, but then chose not to allow to develop to their full potential.
To me the moral aspect is - can they become a person on their current natural trajectory? If it's safely implanted in a uterus then there is a very clear natural path towards personhood. To decide to interrupt that process when a natural path exists is morally problematic to me. But if a someone needs to intervene to put them on the natural path toward personhood then not doing that isn't morally problematic for me.
Yeah, I find conception as a cutoff to not really be consistent due to the nonviability of a wombless zygote. Gametogenesis as a cutoff ("if you can conceive and feed a child you have a moral duty to do so") and implantation as a cutoff ("abstinence, rhythm, condoms, implantation blockers and selective IVF are fine; abortion of an implanted pregnancy is not") are both consistent positions to take, but in-between doesn't really work.
I don't follow: yes, a womb-less zygote will die, but so will a baby who doesn't have anyone around to feed it. Yet nobody argues that the baby has no moral worth because it is dependent on a third party for continued existence, so why should that standard apply to the zygote?
>Yet nobody argues that the baby has no moral worth
False. I do.
However, I am not arguing my own position here; I'm arguing which positions are consistent. As such, that is irrelevant. So:
The dependency of human development on implantation is not merely one of nutrients; it's a marker that activates a whole pile of genetic switches. You can give a blastocyst all the nutrients it wants, but it won't develop beyond that stage. As such, the assembly criterion ("recipe complete, just add food") often given as a justification for conception as a cutoff is only really satisfied at implantation.
There are consistent positions which would make a zygote sacred - but those positions also make ova and spermatozoa sacred, because the partial assembly of the two is the only difference.
I feel like I might as well chime in with my perspective, as someone who has done pre-conception genetic screening for myself and my partner (through Dor Yeshorim) and is currently 7 months pregnant with (hopefully) my first child after IVF (with ICSI). Upfront: I would not consider polygenic screening of embryos for future pregnancies as the technology stands, and only a few specific improvements would push me to reconsider.
Re: Dor Yeshorim, my husband and I checked and were deemed “a match” prior to engagement; that is, for a panel of recessive genetic disorders common in Ashkenazi Jewish background, we were mutual carriers for the disease alleles for none (Dor Yeshorim also offers testing for genetic disorders for non-Ashkenazi Jewish backgrounds, and other genetic testing services for those of Jewish background are available and have some advantages). This was something we both strongly believed offered an excellent cost/benefit ratio due to high background risk and severe disease for affected individuals. If we had been mutual carriers for one or more of these disorders, I expect we would have still married and used IVF with pre-implantation genetic screening for whatever we were mutual carriers for. So anyway, I don’t have a general objection to pre-conception genetic screening (which I used) or pre-implantation genetic screening. I ended up doing IVF in my 20s due to infertility.
When you do a round of IVF, you pay a fairly high price for a very limited number of embryos. I was in many ways an ideal candidate for IVF: at 27, young as these things go, good general health, no identified reproductive issues – only male factor infertility had been identified, and was likely the cause of our low fertility. At my fertility clinic, I paid about $20,000 as a flat fee for up to six egg retrieval and fertilization cycles and unlimited embryo transfers, until such time as I gave birth to a living, breathing baby. A single egg retrieval cycle and one or maybe more embryo cycles would have been somewhat cheaper, but two separate rounds of egg retrieval and fertilization ala carte would have been more expensive, and I couldn’t be sure that I’d succeed in a single round. That price doesn’t include the drugs, which are ballpark $3,000-$5,000 and in my case were substantially covered by our insurance. We did extremely well with our egg retrieval and fertilization: 16 eggs retrieved (just about the sweet spot for generating the highest number of good embryos in a single cycle; many more eggs and the overall quality starts to go down as far as I’ve read), 12 of these fertilized, 8 of those grew to five-day blastocyst embryos (all of which were graded highly, that is, they looked morphologically good under the microscope, which to my understanding at best correlates loosely to successful implantation). One cycle, $20,000, eight good embryos – basically the best-case scenario. Now, implantation – what are the odds there? Again, I’m in good general health, age 27, no ovulation or other reproductive cycle problems identified – and each fairly good-looking embryo transferred has slightly under 50% odds to come through as a living baby (slightly over 50% chance to implant, with about the normal rates of miscarriage or pregnancy loss). My first transfer (fresh, during the same cycle as the egg retrieval) didn’t take, my second (“natural cycle” frozen embryo transfer) did, and I’m now seven months pregnant with no major risk factors or complications.
I was a good IVF candidate and I’m not too squeamish of needles, blood draws, transvaginal ultrasounds, general anesthesia, so the burden of the procedures on me was on the low end. I have six frozen embryos generated at age 27, which are probably on average as good as I am likely to get because quality is expected to diminish with age, and risk of certain genetic mishaps is expected to increase (although for both, probably only marginally over the next few years). My husband and I might want, say, four kids. It’s certainly possible I could have three more healthy pregnancies out of our remaining six embryos, but not a guarantee; if we run out of embryos before we have as many kids as we want, I’ll probably have to do at least one more retrieval and fertilization cycle (preferably before too much more aging – I’d probably consider another round by age 32 if I’m not sure I won’t want more embryos for IVF). If I knew I only wanted one or maybe two kids and I had eight embryos to start with, maybe I’d feel like polygenic screening had some value, as I could expect that one of the top two or three scoring embryos would probably implant and be carried to term. But let’s say I were doing elective IVF for the purposes of polygenic screening and choosing the purportedly lowest risk for several health condition and I had four embryos. The chance that the best of four by polygenic screening fails to implant or results in an early miscarriage is about 50%. If it works, great, I can feel good that I selected an embryo with (possibly) a slightly lower lifetime risk of breast cancer or diabetes. What’s my threshold for the other three not being good enough to transfer and do another round of egg retrieval and fertilization, with associated costs, time, and physical burden (again, even granted that the physical burden on me was probably easier than average)? Consider that taking cells from the embryo for screening has a low but nonzero risk of reducing the viability of the embryo (to the best of my understanding). What if the best two or even three fail to implant?
I was offered genetic and other forms of screening several times, starting prior to IVF and through fertilization and pregnancy. My husband and I declined pretty much all of them. Mostly, I felt like I had done my due diligence in definitively ruling out the most likely (based on ethnic background) most debilitating genetic diseases. Most of what I was offered in terms of screening appeared to target genetic disorders we were very unlikely to carry, and the cost-benefit ratio didn’t seem to favor further screening. For me, some of it was accepting what I did and didn’t have control over by acknowledging that most of the screening offered much more of the illusion of control than actual benefit (which by my best judgment was marginal). I’m not buying into, well, copium. Here? The benefits are slightly lower lifetime risk of a few major health issues, if the polygenic scoring is really as good as purported. I tried looking up what the LifeView site had to offer about their polygenic scoring. The genomic index selection data is only validated for people of European descent, and appears to be generated from and tested on data from the UK Biobank in white European subjects only. That’s not validated in my background. Even if it were, for most of these, the differences are not meaningful to me as an individual who will have only a few kids – 2.6% risk of prostate cancer being reduced to 2.1% is not a meaningful lifetime difference in my eye in comparison to the cost, time, and physical burden. Others may well feel differently, of course. I am interested in what they have to say on polygenic scoring for embryos with an affected sibling or parent. So far they only have data available on this for type 1 diabetes.
Ultimately, I would absolutely not choose elective IVF for the purposes of polygenic screening with the quality of the data available.
What type of screening would I consider – what would bring the benefits up towards being commensurate with the costs and risks? My husband and I came out okay on screening for the genetic disorders we’re at higher risk for by ethnic background, but let’s say my husband and I were both carriers for cystic fibrosis and knew every embryo we generated had a 25% chance of having cystic fibrosis. I’d definitely choose elective IVF and embryo screening in that case. The cost-benefit assessment there seems well in favor of screening. So for polygenic screening, what would I be looking for? Screening with established effectiveness for a few heritable polygenic traits that my husband and I would expect to be at risk for – in our cases, depression, schizophrenia, and probably autism (a word on autism – three of my five siblings have ASD, including two who will probably never be independent adults due to their autism and/or comorbid behavioral issues that are very hard to tease apart from autism and/or exacerbated significantly by the communication challenges posed by autism. I love them just as I love my other siblings and don’t think they should be other than as they are, but no parent wants their child to have that type of barrier to any real form of adult independence, and autism as it has manifested in my immediate family seems to have a high risk for that outcome). For these items I think my children have elevated risk and I would expect more than marginal benefit from polygenic screening – given certain assumptions. At the very least I would want to know that the polygenic scoring for the trait in question has been validated in a population with sufficient data from my ethnic background. More ideally, I want to know if the screening is actually picking up anything that’s actually contributing to my personal risk. I’m not sure this is the way you would want to check this, but here’s my thought process: what is the risk assessment by polygenic scoring on the trait of interest for either parent? If the baseline risk assessed for me and/or my husband for a condition we have reason to believe we have or have risk of carrying substantial genetic contributions for is substantially elevated, it might offer enough information to be valuable to me. Let’s say depression – my husband and most of his immediate family have it, and I and multiple members of my immediate family have had it, either chronically or episodes that required medication. If my husband were given polygenic screening for depression and he scored pretty close to population average, well, that’s a screening that might be valuable in some context, and I would still assume he has highly heritable depression risk, but that test is probably not picking up a genetic signature that corresponds to his depression. So why should it pick up whether an embryo his sperm fertilized has a substantial contribution from his familial risk factors or not? I’d rather my child not have depression, but I can and will accept the baseline risks for depression and a host of other health conditions just like I do the risks for, say, birth defects. That’s something I can accept as part of reproduction; your mileage may vary. If I have reason to believe I’m at elevated risk for something, that may be something I want to control more – but only if my knowledge of elevated risk and the information I can get from polygenic scoring about the contribution to my embryo of the risk factors that bring me so much above baseline line up. On the topic of birth defects, current guidance is that IVF pregnancies have double the rate of birth defects of the heart – something like .7% for natural conception to 1.3% for IVF. It’s still a small absolute risk, but if you’re doing polygenic screening you’re 100% opting into IVF. That itself should be a major consideration to weigh against the current purported polygenic scoring benefits. Anyway, the benefits may well start to line up more with the costs and risks in the future (for my personal calculus, your mileage may vary). For now, this doesn’t even look like playing G-d; this looks like bargaining with RNGesus, and not at a very appealing rate.
I take it the reference to rejecting genetic testing refers specifically to PGT-A (since it sounds like you didn’t have a need for PGT-M).
My understanding is that such testing net increases the likelihood of implantation (i.e. the selection effect less the biopsy effect is positive). Did your research indicate otherwise or was that just not an important consideration for you?
Not an important consideration for me based on my research given my age and my partner's age and the number of embryos generated (and the lack of difficulty in getting to the hormonally receptive state for implantation). My understanding is that the considerations are different mainly for IVF in women a decade or more older than me, who will tend to produce fewer embryos with higher likelihood of abnormalities. Even then my understanding is that the main benefit is knowing sooner whether they are likely to need to try another retrieval cycle to generate an embryo with a reasonable chance at success, because waiting around has an even harsher effect on expected embryo generation difficulty. If I had fewer embryos generated I might have made a different choice. As it stood, my embryos were expected to be of a good enough average quality to get what I wanted, and I was more interested in saving the money and effort.
I'm in a similar situation, but different enough that I think it changes the calculus: I'm doing elective egg freezing just to keep my fertility options open when I'm older, and I'm doing several cycles because I'm paranoid that I'll get weirdly unlucky and/or I'll want a lot of kids. So, at some point I'm going to have ~25 embryos to choose from, at which point polygenic screening starts to look pretty good, especially as it gets better in the next decade or 2. And I've already accepted that I have to do IVF as the cost of delayed child-rearing. I admit the "freeze a crap ton of eggs (or embryos) when you're young, just in case" strategy probably isn't that common though.
This sets off so many alarm bells for me, but to pick just three issues that I haven't seen in the comments so far, this seems like another step down the road to:
- even more expensive and physically and emotionally grueling norms and expectations foisted on women who want to have children "responsibly"
- even more prejudice against disabled and sick people (for existing) and their parents (for allowing them to exist)
both within the medical establishment and in the broader culture
- even more division and acrimony between the socioeconomic classes...
In 2050 Africa is projected to have 2.5 billion people. Presumably very few of them will be able to afford any sort of these genetic tests (to say nothing of poor people elsewhere in the world). And millions (possibly billions) of people will have moral objections to using IVF. If there isn’t enough resentment of elites now, just imagine what will happen after a few generations of selecting embryos for intelligence, health, looks, personality, etc. (Hopefully they can find the genes for humility soon, or else things might get really ugly.)
You can make a parallel argument for the advent of mechanized farm equipment (or proabably any technological advance), ie. more emotionally and physically gruelling norms for non-mechanized farm workers to keep up, more prejudice against human farm owners that refuse to get with the times, more division and acrimony between classes that can/cannot afford mechanical devices, etc.
In fact, we now see the exact opposite: people are valuing organic and hand-made crafts over mechanized products. Humans are not always easily predicted. Of course your points are something to consider for sure, but they strike me as pretty weak predictors and no reason to halt progress.
Ah, yes, the many people willing to loan to the developing world... who can then hand their future children debt burdens to work off, as opposed to the richer IVF babies who will have nothing to work off.
PRS screens are a perfect scam: no proof that they are effective, and no way to prove that they are ineffective for adult onset diseases like schizophrenia for at least 18 years. Go capitalism!
I've been waiting for this post. Some quick numbers I ran the other day to give a clearer sense of how cost-effective polygenic screening is.
Type 2 Diabetes is one of the more common condition for which we have decent polygenic tests. [One study estimated that 40% of Americans will develop type 2 diabetes at some point in their life](https://www.webmd.com/diabetes/news/20140812/40-percent-of-americans-will-develop-diabetes-cdc-projects). The number of years of life lost to type 2 diabetes varies quite a bit depending on the age at which one develops the condition, but [this study found that even among older men and women, they lost 11.1 and 13.8 Quality Adjusted Life Years respectively.](https://jamanetwork.com/journals/jama/fullarticle/197439). This article suggests the average age of onset of Type 2 Diabetes is [45 years](https://www.medicalnewstoday.com/articles/317375), though the "source" here is just a caption under an image, so take this with a grain of salt. Regardless, let's assume that 15 QALYs is a reasonable estimate for the number of years lost by Type 2 Diabetics.
The value of a QALY varies, but [this article suggests that in the US we value a QALY at somewhere between $50k-$150k. Let's use a fairly conservatie estimate here of $50k.
The average US diabetic in 2013 spent [$85,000](https://pubmed.ncbi.nlm.nih.gov/23953350/) in direct medical costs over a lifetime (about $100,000 in today's dollars).
Add these two up, and Type 2 Diabetes costs the average American diabetic $835,000. With a 4 in 10 chance of getting type 2 diabetes at some point in one's life, the average future American will lose $334k to type 2 diabetes.
Using [Shai Carmi et al](https://github.com/scarmi/embryo_selection)'s code for estimating the relative risk reduction from selecting the two best embryos out of a batch of 10 for a disease with prevalence of 0.4, whose variance we can explain roughly 11% of with polygenic testing, it looks like the first embryo would get an expected risk reduction of 13.7%, while the second would (probably) get a risk reduction of around 10%. At $835,000 of lifetime costs, this works out to a total value of about $200,000 just for Type 2 Diabetes risk. It's possible the 40% lifetime risk I found in the article linked above is high. But even if the risk is only 20%, it's still worth $136k. And the true value is likely to be higher because adding more traits will always increase the expected value.
[CNY sells normal IVF services for $16,000](https://www.cnyfertility.com/ivf-cost/). With a $1400 starting fee and a $400/embryo screening fee (the cost last time I checked in on LifeView), the additional cost from screening would be $5400, bringing the total to $21400. In other words, you could pay $21,400 to get a lifetime benefit of $200,000 for your children. For a life of 85 years, that works out to a 2.7% annual return by the time your children die (though it's likely the return would be somewhat better if we included other diseases).
There's something to be said for the non-fungibility of health. The most expensive medical care in the world can only do a limited amount to extend the lifespans and improve the health of diabetics. And the same is true for nearly all chronic conditions that can be screened for with polygenic testing. So even if you skipped IVF + polygenic screening for your children and invested $21k into index funds, the $6 million valuation it would have by the time your children reached retirement age probably couldn't be turned into an additional 5 years of healthy life.
Your estimate for IQ gain is actually off: using results from [EA3](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985927/), we can explain roughly 10% of variance in intelligence from genetic testing. Using Gwern's own code, we can estimate a gain of 5.5 IQ points when selecting the best of 10 embryos. I suspect Gwern was using results from EA2, which only explained 4.5% of variance. With 34 embryos (the amount the couple in the article you linked had to choose from), we would expect a gain of roughly 7.4.
My overall conclusion is that if we somehow end up banning pre-implantation genetic testing it will be one of the worst decisions we have ever made. The impact would be on-par with a worldwide ban on vaccines or sewage systems. It would likely cost the average person around 5 years of healthy life. In fact I think it will be so bad for the citizens of a country that anyone who can afford to will probably leave to get it done elsewhere, since the cost of the plane flights to get IVF done will be trivial compared to the lifetime benefits of reducing polygenic disease risk.
And the math looks more compelling the further out we extrapolate. There's several research labs working on creating egg cells from induced pluripotent stem cells, which in turn can be created from skin or blood cells. If someone manages to get that working it may eliminate two of the biggest drivers of IVF cost: medication to stimulate egg production and surgical extraction of the eggs by a specialist doctor. Producing and screening embryos at that point would be as simple as submitting a cheek swab and a sperm sample and signing some consent forms. The only remaining necessary procedure would be frozen embryo transfer, which is typically less than $1000.
At that sort of price level I suspect we would see embryo screening become a routine part of pre-pregnancy care. Every generation would have lower chronic disease risks, higher healthy life expectancies and greater intelligence. At least it might continue for a few generations before we hit the singularity. After that who knows what will happen.
Hello Gene, my name is Laurent, I'm the CEO of Genomic Prediction. We've been doing a similar calculation, using similar methodology. Would you be interested in contacting me to discuss a potential collaboration? contact@genomicprediction.com
Most parents have around two kids. It seems likely that parents who go through IVF to reduce their child's disease risk are likely to have all of their kids through the process. So it makes sense to assume they will implant the two embryos with the lowest risk of disease.
Ah right, thanks - I didn't realize embryo freezing was a possibility! Funny to think that there are people who were conceived years before their birth.
It may be worth saying explicitly that from "polygenic testing and picking best-of-10 will on average reduce the risk of type 2 diabetes by 14%" and "polygenic testing and picking best-of-10 will on average increase IQ by 5 points" it _doesn't_ follow that polygenic testing and picking best-of-10 will on average reduce the risk of type 2 diabetes by 14% _and_ increase IQ by 5 points. You can pick one or the other, or some combination of both that does both less effectively, but you can't get them both at once. Screening for more traits will let you do more, but never all that much: by any criterion of "best", the best of 10 embryos from a given pair of parents isn't likely to be _that much_ "better" than the average from the same pair. And, given that some embryos fail to implant, actually it's just as likely to be the second-best or maybe the third-best.
(I'm not specifically saying that PGS shouldn't be done or isn't worth it, just cautioning against combining figures overoptimistically.)
The paragraph that starts with "My overall conclusion" does not actually follow from anything you wrote above; your analysis merely told you how to gain like 2.7% interest rate on $20k, which is not all that much. One might easily read your analysis and conclude that IVF is not worth it, then you conclude it's a better invention than SEWAGE SYSTEMS?!?
I can't believe Scott linked to this nonsense.
To pour some cold water on all this hype: IVF caries risks, risks that everyone involved in these discussions seems to ignore. Other than the risks and discomforts to the mother from the procedure, IVF babies have more of most types of defects and diseases. Now, we don't know whether IVF, when performed on normal-fertility women, results in a decrease in health of the baby; maybe it's all confounders. But everyone knowledgeable only recommends to do genetic screening IF YOU ARE ALREADY DOING IVF FOR OTHER REASONS.
I am not aware of anyone knowledgeable that recommends IVF+genetic screening for mothers with no fertility issues who can conceive without IVF. Gwern himself does not recommend this.
Agree with LGS' concern about the overall conclusion. I do appreciate the effort that went into the post and it seems plausible IVF is highly valuable. But effort that can justify a weaker claim is no reason to make extreme claims without further evidence.
The conclusion clearly does not follow from the content in the post. Even on the most optimistic mentioned assumptions, 15 QALY lost to diabetes on average, 40% diabetes incidence, 15% reduction by IVF screening, *100% of people in the world getting IVF* we only get 0.9 QALY average increase. Still great, but not 5 years.
Maybe a lot more could be gotten from screening against other diseases too. And presumably that's where the 5 year idea comes from?
But note on the other hand that there are studies estimating that curing *all* cancer and heart disease - the two biggest killers- would only give us 6 more years to live. Given that it seems highly unlikely IVF could get that far. See https://www.latimes.com/archives/la-xpm-1990-11-02-mn-3743-story.html
Preimplantation genetic diagnosis (PGD) has been in use for years, and many children have been born thanks to it. With that in mind, how is last year's birth of "Aurea Smigrodzki" through preimplantation genetic testing for polygenic (PGT-P) significant?
I've never seen "PGT-P" before, and Google didn't reveal any sources that explained how it was different from PGD.
PGT-P can screen for a much much wider variety of traits. Previous PGD really only looked at chromosomal abnormalities like Down Syndrome and single-gene genetic disorders like Sickle Cell Anemia and Tay Sachs. PGT-P can assess heart attack risk, breast cancer risk, diabetes risk and others.
The tests they use for this still only explain ~10% of variance for most traits, but this is enough to get a 50-60% reduction in the risk of a single disease when selecting from among 10 embryos (or 20-30% for several diseases when selecting for lower risk of multiple diseases).
PGT-P is a subset of PGD. PGD emcompasses all types of genetic testing. Traditionally that included aneuploidy testing (down syndrome etc), monogenic disease testing (sickle cell anemia, Huntington's, Tay-Sachs etc). Recently companies have started offering miscarriage risk, structural rearrangement testing, polygenic disease testing. But they're all PGD.
Full disclosure, I believe human life (and personhood) begins at conception. So the whole concept of deliberately creating lots of people in order to pick one and kill the rest is pretty horrifying to me.
But for the rest of you, consider this issue. What happens when the parents who paid thousands of dollars to pick the "perfect child" discover that their child is just as human and imperfect as the rest of us?
Also, try listening to the adult children of donor conception and IVF. A lot of them do not appreciate being purchased.
FYI, IVF works by selecting embryos *before* conception, then choosing a specific one to implant sperm into. Each embryo is about as much as a person as a woman's period is (that is to say, by most moral systems, not at all.) If IVF was sex-selective abortion it would be far more of a culture-war flashpoint.
Surely this can't be right. (At least, not if talking about the sort of polygenic screening discussed here.) Before conception, what you have isn't an embryo, it's separate eggs and spermatozoa. When they say "pre-implantation" it doesn't mean "before implanting sperm into egg", it means "before implanting fertilized egg into uterus". I guess you can do a bit of genetic screening on unfertilized eggs, but it will be much less effective than doing it on fertilized ones, and e.g. all the calculations Gene Smith did above are assuming that it's fertilized eggs -- embryos -- that are subject to screening.
It's true, and interesting, that IVF attracts much less anger than (ordinary) abortion. But e.g. the Roman Catholic Church officially condemns IVF, and so do at least some evangelicals.
Oh wow, I did not realize that. Had always assumed that IVF was pre-implantation and that it was easy to simulate the genes of the resultant embryo caused by implanting a specific sperm into a specific egg. If genetic screening on unfertilized eggs is much less effective, why?
Actually, I don't know whether it's even _possible_. You'd need to read out all the contents of the egg's DNA without damaging the egg, which sounds impossible to me, and do the same for the sperm, which sounds even more impossible.
What they actually do is to _remove one cell from an embryo_ and look at its DNA. I'm pretty sure this destroys that cell, but the process of embryo development doesn't seem to be disrupted as a result.
Like Nancy, I would be interested in more information about these "adult children of donor conception and IVF" and what exactly it is they object to. So far as I can tell, most people in that situation are as glad to be alive as anyone else, and I don't see how they're "purchased" any more than (say) someone who would have died shortly after birth if it weren't for a hospital's (possibly expensive) neonatal intensive care unit.
As for your question: if anyone thinks they're picking a "perfect child" or a child who's something more than human, then they're either being deceived or deceiving themselves, and in that situation they're liable to be disappointed. But "it's possible for people to be deceived about X and then disappointed" is no argument against X, because it's true for _everything_.
What a more reasonable parent might think, if the sort of thing discussed here becomes common, is that their children are _less likely_ to (say) develop diabetes than they would have been with a more traditional conception process. In that case, your argument has the same structure as this. "What happens when, having paid thousands of dollars more for a more reliable car, it breaks down anyway?". The answer, obviously, is that (1) when that happens you'll be disappointed, but (2) when it _doesn't_ happen you'll be glad, and the hope is that the thousands of dollars make #2 happen more often and #1 happen less often. Similarly, if you pay thousands of dollars in the hope that your child will be less likely to get diabetes, then (1) if they do you'll be disappointed and (2) if they don't you'll be glad, and the hope is that _on balance_ the embryo-selection thing makes #2 more likely and #1 less likely.
(Maybe it will turn out that it doesn't work so well. In that case few will be willing to put up with the cost and inconvenience. And maybe it'll work fine but be the moral equivalent of mass murder. In that case we shouldn't do it, but it seems most people don't agree with you on that point, and for what it's worth I also don't. I will, like you, refrain from getting into an argument about that contentious question, but I will suggest that you consider the folllowing thought experiment: Suppose that at one of these clinics there is a fire, and a nurse carrying a tray full of newly fertilized embryos is in danger of not getting out before the flames overwhelm the building. Which would be the greater tragedy: for the nurse to get out with the tray of embryos and then die of her burns, or for the nurse to leave the tray of embryos behind but get out safely?)
Worry about large-scale ill effects of gene screening seems to be based on an assumption that there will be a consensus about what gets screened. My bet is that if there is large-scale screening, there will be a number of organizations doing it and in the nature of things, they won't all be using the same screens. They might even go about screening for the same genes in different ways with different effects. Does this take some of the edge off?
Yes, this is my daughter Aurea's photograph, not stock. Thanks for writing about polygenic testing, this is a revolutionary medical technology and yet many oppose it. Note: I do not have any commercial or professional involvement with PGT-P, my GF and I just happened to be the first couple to successfully use the technology. The more parents know about it, the sooner it becomes standard medical practice, which is a good thing, since (as I see it) it leads to Lake Wobegon, not to GATTACA.
Most parents raise two or more children. It appears likely that parents who use IVF to lower their child's risk of disease will probably use the procedure for all of their children. Therefore, it stands to reason that the two embryos with the lowest chance of illness will be implanted.
O brave new world, that has such people in 't!
Hug me, 'till you drug me, honey; kiss me, 'till I'm in a coma!
https://www.nejm.org/doi/full/10.1056/NEJMsr2105065?query=recirc_inIssue_bottom_article
Selecting for intelligence feels likely to be banned (unfortunately as this could be hugely beneficial for humanity if widespread) but in theory selecting against disease should also be pro intelligence as both are correlated through mutational load, right?
Given the prices involved here and methods used, this might be...really difficult to ban? If you let parents see each embryo's data before they make a choice, and the information necessary to make that selection is on SciHub, then, uh, *wink wink*...
Would be hard to ban any use of this method considering how many diseases it can fight (and how sympathetic people suffering from these diseases are), and I think any use of this method quickly results in selection for whatever parents want (whether that's intelligence or aesthetic traits).
Yeah, I agree. In fact, I don't know if you even need the data. Here's an article I saw linked over at marginal revolution a while back:
"Children resulting from frozen embryos were more socially adept than those implanted fresh after eggs were fertilised. The children also moved better, had superior communication skills and showed more independence. Allan Pacey, a fertility expert at the University of Sheffield, suggested that this was caused in part by the rigours of the thawing process. Not all embryos survive thawing, and perhaps those that do are “stronger”, he said.[11] Perhaps freezing and thawing embryos is an inadvertent eugenics process, most successful with embryos having a low mutation load."
https://quadrant.org.au/magazine/2015/05/eugenics-ready/
There does seem to be a selection process, post implantation.
"Good obstetric outcome (GBO), defined as a singleton, term, live birth with appropriate for gestational age birth weight, was the primary outcome measure. Secondary outcomes included live birth, clinical pregnancy, spontaneous abortion, preterm birth, multiple births and gestational age-adjusted weight. Outcomes were modeled using the generalized estimating equation approach.
MAIN RESULTS AND THE ROLE OF CHANCE
"Overall, fresh transfer was more likely to result in a live birth (55.7% versus 39.5%; adjusted risk ratio 1.21; 95% CI 1.18–1.26; P < 0.001). "
https://academic.oup.com/humrep/article-abstract/35/12/2850/5982008?redirectedFrom=fulltext
Interesting; so it sounds like they found the opposite: fresh beats frozen.
Well, I'm not sure they're not entirely "opposite" results. If freezing meant embryos with problems were less likely to develop to term that would explain the improved health outcomes from frozen infants.
I'm saying that in contrast or addition to the Marginal Revolution advanced hypothesis "Not all embryos survive thawing" it could be that thawed embryos with health issues are less likely to be delivered to term.
If the observations are all accurate then I really wonder what mechanism mediates this.
That makes me wonder-- is freezing merely a mechanism to improve outcomes for IVF, or can it be used to improve outcomes even relative to non-IVF natural conception?
That is, would it make sense for couples to freeze embryos specifically to filter out worse ones (aside from the usage of PGS)?
If it's banned in the US but legal in, say, Brazil, then presumably a lot of wealthy ambitious couples will go on a long vacation (or several short ones) in Brazil and come back with the woman pregnant, and regulators in the US unable to do anything about it.
Citizen jurisdiction. They might not be able to force the woman to have an abortion ("cruel and unusual"), but a country can absolutely throw its citizens in prison for what they did abroad.
(The USA in particular also has some really dodgy long-arm statutes which give them jurisdiction if any money touched the US banking system at any point.)
If they can find it out.
I hope the Overton window shifts enough that selecting for intelligence gets accepted -- I always think of this passage by Nick Bostrom in https://www.nickbostrom.com/views/science.pdf:
"There are three ways to contribute to scientific progress. The direct way is to conduct a good scientific study and publish the results. The indirect way is to help others make a direct contribution. ... A third approach is to marry the first two and make a scientific advance that itself expedites scientific advances.
A “superficial” contribution that facilitates work across a wide range of domains can be worth much more than a relatively “profound” contribution limited to one narrow field, just as a lake can contain a lot more water than a well, even if the well is deeper.
No contribution would be more generally applicable than one that improves the performance of the human brain. Much more effort ought to be devoted to the development of techniques for cognitive enhancement, be they drugs to improve concentration, mental energy, and memory, or nutritional enrichments of infant formula to optimize brain development.
Imagine a researcher invented an inexpensive drug which was completely safe and which improved all‐round cognitive performance by just 1%. The gain would hardly be noticeable in a single individual. But if the 10 million scientists in the world all benefited from the drug the inventor would increase the rate of scientific progress by roughly the same amount as adding 100,000 new scientists. Each year the invention would amount to an indirect contribution equal to 100,000 times what the average scientist contributes. Even an Einstein or a Darwin at the peak of their powers could not make such a great impact. Meanwhile others too could benefit from being able to think better, including engineers, school children, accountants, and politicians."
"Imagine a researcher invented an inexpensive drug which was completely safe and which improved all‐round cognitive performance by just 1%"
Sounds like modafinil to me
Nah, that's temporary. A better comparison is salt iodization: https://www.givingwhatwecan.org/post/2016/01/are-we-underestimating-benefits-salt-iodization/
But interventions like salt iodization only help better realize potential, not increase it. It's the latter I'm curious about. Unfortunately this is a really really hard problem: https://www.gwern.net/Drug-heuristics
Practically, what's the difference between "realizing" potential and "increasing" it? Is it the upper bound of what's possible? I don't know if we know what that upper bound looks like for polygenic testing for either a given individual or a population.
Yes, the main difference is about the upper bound. Addressing iodine deficiencies (from the limited reading I've done) is likely to be a very cost-effective method to improve cognitive ability in the developing world. I think it's a shame we don't prioritize these types of low-cost interventions that have such huge long-term effects.
In regards to your second question, the upper bound for polygenic testing for a single generation is about 1 standard deviation for any given trait given current limitations on oocyte production and GWAS sample sizes. For most diseases it's closer to 0.3-0.5 standard deviations.
For multiple generations the limits are much much higher. For example, Steven Hsu has estimated that if you naively add up all the alleles that contribute positively to IQ, additive variance alone would predict that genome would have an IQ of about 1000. Obviously in practice that wouldn't work even if you could do it because at some point the relationship between positive alleles and phenotype would break down. But it gives you an idea of what might be possible in the future.
Further evidence can be found in animal and crop breeding programs that have been going on for thousands of years. We have increased the oil and protein content of the ancestors of modern corn by 30 standard deviations over the last 10,000 years. And while humans are not corn, many of the genetically influenced traits we care about (like disease risk) are controlled by a similarly large number of genes (meaning they are probably capable of undergoing similarly large increases with enough selection pressure).
"For example, Steven Hsu has estimated that if you naively add up all the alleles that contribute positively to IQ, additive variance alone would predict that genome would have an IQ of about 1000."
We seem to agree that that wouldn't actually work. So doesn't that indicate a problem with the model we're using? We do agree that not all improvements are additive, right? Some may just be different ways of accomplishing the same thing.
I feel like it's hard to predict whether this technique could produce people who were that much faster, better, or stronger than the best currently existing humans without some kind of tradeoff. Eventually we'd presumably start running into issues related to cranial capacity. Or trading off generalized for specialized intelligence.
The notion of "+.2 IQ points for this gene with no consequences or costs" just seems deceptively ... neat and predictable.
"Further evidence can be found in animal and crop breeding programs that have been going on for thousands of years. "
Sure. And the Green Revolution has accelerated that improvement with fertilizers, pesticides, watering, etc. It's also produced plants that don't survive well outside of a farm. It's produced plants that serve humans rather than themselves (since obviously wild plants have had millions of years to improve themselves for their own purposes.) Whats the equivalent of applying that metaphor to humans? Being able to use more fertilizer and water, as provided by farmers, is win-win. Maybe human intelligence can do something similar. More food = more cholesterol for neurogenesis? But then, we've demonized cholesterol and we give people drugs so they produce less of it so they can live longer. At some point crop improvements are going to have to hit some kind of physical limit in terms of photosynthetic efficiency and available light. Even if per hectare crop production is not yet leveling off for some crops. Monoculture offers a benefit in terms of being able to harvest ripe crops at a set time, reducing poaching by animals. But the loss of genetic diversity also increases vulnerability to pathogens. Genetic diversity exists for a reason. IQ positively correlates with alcoholism, for example.
An endurance runner has more slow twitch muscles. A sprinter has more fast twitch muscles. Once we eliminate various physiological defects, further improvements are tradeoffs. And I don't know how to be certain that this wouldn't be an issue with polygenic testing.
Polygenic testing is a very exciting development. It can help address things like increasing mutational load in an ethical fashion. But we're dealing with self modifying systems whose behavior we can't fully predict or understand. That seems like a setup for surprises.
I think talking about Overton windows is rather premature at this point, as there's no hard evidence that embryos can be effectively screened for intelligence at all. Merely assigning a numeric score based on a bunch of markers isn't very reliable for an extremely polygenic trait such as intelligence... especially when there's still active debate going on regarding what proportion of IQ is genetic; and even to what extent IQ correlates to real-world outcomes; or whether it even makes sense to use a single scalar quantity to answer such questions.
It’s 85 percent heritable (g), not iq scores. Especially at adult-age. Less suppressed variation due to being forced to go to school or parental choices. Cumulative exponential effects from learning faster and gaining skills faster. Same reason why bad diet in NKorea attenuates and reduces intragroup variation. Phenotypic variation is maximized and potential is realized when opportunities are maximized; sex-linked behaviours, career choices, intelligence, anything. Breeding dogs and animals have exact morphological similarities as hybridization of haplotypes or human breeding groups, it’s just politicized and suppressed because the repercussions are too big to be accepted (non-conscientious, psychopathic, low intelligence being a feedforward loop of more undesirable societal outcomes and offspring). And au contraries to the many individual variant effect hypothesis, it’s mainly few main progenitor genes with integrated mechanisms that are deterministic of neurological/biophysical health that are conserved with additional improvements made by a combination of rare and minute pathways that increase the efficiency/differentiation of brain tissue/change of rate of growth and thickening which increases the magnitude of intelligence gains. Not just a series of 0.00012 percentile variants that improve myelination or conductivity. dendrite dispersibility. Scalar measurements are invariant with respect to any and all cognitive tasks. More instructions, more complexity is inversely proportional to success rates; that includes taking medicine, making mistakes, accidents or anything. Statistical artefacts are also irrelevant and impertinent. China will be dominating and probably Israel too. The elite population has already been practicing eugenics discretely with IVF reiterated embryo selection and cross marriages stratified only by high conscientiousness, agreeableness, intellect and desire for dominance.
Relevantly Israel is leading the world in IVF so they will probably be the leader in embryo selection: https://www.nytimes.com/2011/07/18/world/middleeast/18israel.html
Judaism is bioethically permissive (abortion is legal in Israel, no one cares) and there isn't much wokeness, and there is a national defense reason to add +10 IQ to everyone so I expect them to be first or among the first to do embryo selection.
I did see an opinion poll of China; they're not actually for it. See https://www.pewresearch.org/science/2018/07/26/public-views-of-gene-editing-for-babies-depend-on-how-it-would-be-used/ and https://www.pewresearch.org/science/2020/12/10/biotechnology-research-viewed-with-caution-globally-but-most-support-gene-editing-for-babies-to-treat-disease/
https://www.theguardian.com/world/2019/dec/30/gene-editing-chinese-scientist-he-jiankui-jailed-three-years this also happened in China so I wouldn't count on it and most Taiwanese/Singaporeans are against embryo selection for intelligence (>60% against, ~30% for) so I don't think it's popular in China.
You don't have to understand all of the genes in order to select for higher intelligence. It may be extremely polygenetic, but we can still identify the gene variants with the largest effects and select for those. I think the Overton window is very relevant, since we're going to have the technology to attempt it long before we know whether it's actually possible.
To know if we can select for intelligence, we'd basically need to just do it on a massive scale in humans, then compare the IQs of children selected for intelligence to children not selected for intelligence (and obviously account for the many, many confounders). The question is whether we allow this experiment to take place or not.
> It may be extremely polygenetic, but we can still identify the gene variants with the largest effects and select for those.
As of today, we really can't do that, because intelligence is not just a linear combination of a bunch of genes. Like any polygenic trait, it's a complex network of interactions between genes and regulatory regions, all of which upregulate something while downregulating something at the same time. So assigning an IQ score based on a bunch of markers is not a simple matter of multiplying their association scores together. It's a search in multi-dimensional space, and the problem with brute statistical models -- yes, even ML models -- is that if you have enough dimensions, you have enough degrees of freedom to pretty much find anything you want.
As I said in my comment above, if someone had a model that provably selects embryos who then grow up into children who reliably perform better in the real world than controls, then I would be impressed. But merely throwing GWAS at the wall to see if it sticks is less interesting to me.
> Like any polygenic trait, it's a complex network of interactions between genes and regulatory regions, all of which upregulate something while downregulating something at the same time.
It's true of course that the genetics of intelligence are complicated. But you're incorrect in saying that this makes it impossible to select for. Most of the variance in highly polygenic traits can be explained with linear effect models. See this paper for a more thorough analysis: https://www.biorxiv.org/content/10.1101/2020.02.12.946608v1.full
> if you have enough dimensions, you have enough degrees of freedom to pretty much find anything you want.
Only if you use a weak statistical threshold for significance. But most modern genome-wide association studies use a very strict significance threshold of 5*10^-8, at which point you don't get many false positives.
> But merely throwing GWAS at the wall to see if it sticks is less interesting to me.
This is not an accurate description of how polygenic screening is done. All of the predictors used by companies currently doing pre-implantation screening are validated using test sets of siblings that weren't in the training data. And while the predictors used today don't capture all genetically caused variance (usually they capture around 20% of it), they do significantly better than chance at picking out the sibling who will go on to avoid developing a tested disease.
There are some limitations to these results (for example predictors of disease risk created with a training set of people with mostly European ancestry don't generalize well to non-Europeans), these limitations are essentially due to differences in the frequencies of certain alleles among populations whose common ancestors are sufficiently distant.
This in turn is caused by something called "linkage disequilibrium". When DNA from a sperm and egg crosses over during meiosis, the locations of such cross-overs are essentially random. But more often than not, base pairs on the chromosomes that are physically very close to one another on the genome will remain together after crossing over. This creates a problem for geneticists: if you're trying to figure out which letter in a protein-coding region is causing a 2% increase in risk of breast cancer, how do you know whether it's the A or the T right next to it? They're almost always inherited together due to linkage disequilibrium.
For people with recent ancestors, this doesn't have much of an effect on the prediction accuracy of these GWAS tests; the A and the T are very likely to be inherited together, so no matter which one was causing the increased risk of Breast Cancer, selecting against one will probably select against the other. But the longer ago two people last shared a common ancestor, the more likely it is that one of their ancestors had a split between those the letter that actually causes the change and the one that you've pinpointed as most likely to cause it. If that happens, your predictor becomes useless because it's incorrectly assigning causation.
Fortunately there's a solution. In the short term with the relatively small sample sizes we have today, we can restrict predictor use to populations in which they have been validated to work well. And in the longer run, GWAS need to start including genetic/phenotype data from a much larger, more genetically diverse group of people. Doing so will both improve the predictors AND make the benefits of embryo screening available to a larger group of people. And we're likely to develop many useful screening tests along the way that can be used to target health interventions at people most at-risk for certain conditions.
I don't think something has to be achievable for there to be a productive discussion about Overton windows. Five years ago self-driving cars were a novelty that still to this day don't function well enough for commercial use, but there were all sorts of ethical discussions around their decision making that helped create a societal opinion about the technology. Similar discussions take place all the time with the potential problems/benefits of AI and how we should approach the technology.
Boosting human intelligence through this type of gene selection is a bit further off than some of these things, but the potential is there for it to arrive within our lifetimes, and discussions about it will surely happen before it is fully feasible.
>Five years ago self-driving cars were a novelty that still to this day don't function well enough for commercial use, but there were all sorts of ethical discussions around their decision making that helped create a societal opinion about the technology.
I'm pretty sure that the "societal opinion about the technology" is that society expects the technology to produce cars that simply do not crash, and that nobody who matters is going to say "It's great that our cars make what we consider proper ethical decisions about who or what to crash into". The consequentialist nerds got to imagine that the Trolley Problem finally had a real-world application; everybody else said "if you're talking about what the car will decide to crash into, get back to us when you've got the car deciding not to crash".
Anything that avoids anyone mentioning the trolley car problem ever again is OK in my book
We already know polygenic scores can predict which sibling has higher intelligence and educational achievement. Predicting which embryo will is no different.
> ... A third approach is to marry the first two and make a scientific advance that itself expedites scientific advances.
I thought that was going to be "A third approach is to marry the first two so they have more scientist kids."
Strange loop is strange.
If having 100,000 more scientists made a huge difference, we would *already* have seen that effect, since there are *way* more scientists working today than at any time in human history, even on a per capita basis. If it made a giant difference, we ought to be seeing Einstein/Fermi/Newton breakthroughs on an annual basis, certainly much faster than we saw them before 1939 -- and nothing could be further from the truth.
The entire calculation is based on a dubious premise about the nature of scientific advance, id est that it proceeds like some kind of construction of an earthen dam, and if you have 200,000 peasants with buckets it gets done 2x as fast as if you had only 100,000. But so far as I can see, an examination of history suggests quite the contrary, that science advances largely by abrupt and difficult to explain (let alone predict) highly contingent paradigm shifts that are the result of some lucky coincidence of improved instrumentation, cultural readiness for a paradigm shift, and some well-prepared brilliant mind that happens to be born at the right time in the right place. You might say it happens by quantum transitions, like absorption of an visible photon to cross a band-gap, and in such a case it doesn't really matter how many IR photons with energy much less than the band gap you provide, nothing happens until the big hv comes along.
> If having 100,000 more scientists made a huge difference
I think you're thinking of "huge" in relative terms, while Bostrom (and I) think of it in absolute terms. Like how a billion dollars is a huge amount of money, but negligible vs say Apple's market cap. I agree in relative terms it's small, especially given that (to quote Scott) "constant growth rates in response to exponentially increasing inputs is the null hypothesis" (https://www.lesswrong.com/posts/v7c47vjta3mavY3QC/is-science-slowing-down). It's still a lot larger than the first 2 sorts of advances, usually.
I agree with the content of your second paragraph, but am puzzled by how it wouldn't be affected by talent pool size (whether size = number of people or "amount of talent", eliding difficulties in aggregating talent for this to be measurable).
It's affected by the talent pool size up to the limit of saturation, but not afterward. Think of enzyme kinetics: once you saturated the enzyme, you don't get any more product by boosting the substrate concentration, because the substrate concentration is no longer the limiting factor on the rate.
So the question is: have we reached saturation on the talent pool yet? That is, is everyone who *can* do scientific breakthrough thinking identified, recruited, and remunerated sufficiently that the availability of talent is no longer the limiting factor? I think a decent case can be made for "mostly yes." You don't really see much in the way of Ramanujans escaping otherwise impoverished lives by sheer luck (writing a letter to Hardy). We're pretty darn good at identifying people who have the requisite smarts and easing their way into the field if they want to be in it. (With some caveats, of course: I'm amused that the woman who was one of the pair that invented the modified-nucleoside tech used to make the mRNA COVID vaccines had a rough time at Penn and ended up leaving because people thought she was an unproductive crank, and now there are people calling for her to share the Nobel for the work.)
That begs the question of what the limiting factor might be, if it isn't the size of the talent pool. As I said below, I don't have any strong ideas on what it is, other than some vague feeling that resources are not quite distributed right, that the *most* talented of the talent pool are getting the most time/money to do their work, a the expense of the less talented. (And here I mean "talented at producing breakthrough ideas.") But I have no idea how to identify such people algorithmically, although I tend to feel I can spot them when I meet them -- it's a certain weird independence of thought, an ability to spot the weakness in the conventional wisdom. It's the person who says "this phlogiston theory is all well and good, very logical and explains a lot, but I wonder what happens if I oxidize some mercury."
Hmm, thanks for the food for thought, I think it's persuasive.
re: what the limiting factor may be, perhaps this Fast Grants postmortem is relevant -- its authors include Tyler Cowen and Patrick Collison: https://future.a16z.com/what-we-learned-doing-fast-grants/
Sample quote:
"A common theme across all of these is that fairly obvious opportunities were not pursued by incumbent institutions. We give examples of actions Fast Grants took not to indicate some kind of supposed brilliance but rather to emphasize the opposite: Fast Grants pursued low-hanging fruit and picked the most obvious bets. What was unusual about it was not any cleverness in coming up with smart things to fund, but just finding a mechanism for actually doing so. To us, this suggests that there are probably too few smart administrators in mainstream institutions trusted with flexible budgets that can be rapidly allocated without triggering significant red tape or committee-driven consensus."
For the sort of science that needs a research laboratory to be done properly, the limiting factor is probably the supply of research laboratories. Fully stocked, staffed, and maintained research laboratories are not cheap, and lots of people who aspire to be and have the education/credentials to be scientists seem to never land a position in one (except maybe as chief bottle-washer to a "real" scientist).
There's some science that can be done just by staring into a coffee cup and thinking real hard, https://www.beanthinking.org/?p=1019, or maybe poking at the keyboard of a commodity PC. But there's a great deal more science that deceptively seems like it should be this sort of science, but veers rapidly into junk if not grounded by experimental verification and model validation. For which, you need research labs, and if you exceed the research-lab limit you just wind up with lots of wannabe scientists thinking up junk science.
> I think a decent case can be made for "mostly yes."
I think it's "almost certainly not". The internal politics, incentives and funding structures around science are pretty perverse, and I think this drives a lot of talent away.
Aren't you a hard hitting outfielder for the San Diego Padres?
Shhh. I get a little bored with just hitting and throwing a ball, sometimes, but management doesn't approve of moonlighting.
I would like to challenge your central premise: that we aren't seeing more scientific development than ever before.
Medicine is the classic example. Today there are people studying and creating scientific breakthroughs on rare diseases. We lay people don't see this unless we have a relation struck by this rare condition. These are really hard, breakthrough discoveries that save lives. Are they society changing? Yes, if it's your loved one.
Without all these scientists you couldn't focus on rare diseases. To society at large, these are relatively minor and, to be honest, insignificant improvements most of the time (but can lead to breakthroughs: https://labblog.uofmhealth.org/rounds/10-studies-highlight-importance-of-rare-disease-research)
Yes we haven't learned how to increase our rate of Einsteins (not sure I agree but I'll accept it), but the breadth across disciplines and niches that we are advancing human knowledge today is unprecedented.
I'm not sure, but I don't think I agree with that. If we consider advances in the context of what already exists, and the resources available for implementation, I think a strong case can be made that there are many periods of history in which general technological advance was significantly higher -- and was reflected in a much strong rate of general social improvement. Let's say the advances in chemistry, thermodynamics, engineering, metallurgy and civil engineering in the 1600-1700 timeframe, for example. Or even the advances in physics in the 1880-1950 timeframe.
I agree biochemistry or molecular biology is having a renaissance right now, but I don't agree that's due to the number of people working in it. Those advances are largely built on factors that were invented 50 years ago -- breakthroughs in instrumentation (NMR) or technique (PCR), or brilliant insights (Watson-Crick model). The surge of people into the field in the last 20 years is I think a "Gold Rush" like *consequence* of smart people realizing the intellectual endeavors in this field might pay off better than in others, rather than the reverse.
I've been in the business (science research) a long time, and my anecdotal observation (insert the usual caveats) is that advance really is a lot like spectroscopy in quantum world: to go from Here to There, where There is some nontrivial and significant advance, it usually seems a quantum event, someone has to just take one big jump, all at once, and it simply can't be duplicated by any number of people taking any number of small jumps.
There are far more scientific papers published today than were published when I started in the business in the 1980s, but I would be hard-pressed to say that the density of genuinely transformative ideas has increased. We may have essentially hit "saturation" in the sense that throwing more (random) people and money into the process won't get us anything but more chaff, not any more wheat. It's not really the rate-limiting step any more.
What is, though? I don't know. I would vaguely say "getting money/time into the *right* hands -- of people who are capable of genuine breakthrough thinking." Problem is, they're really hard to identify. The guy who invented PCR is basically a surfer bum. There are plenty of people who had one brilliant idea and did zip before and after. It seems deeply serendipitous in many (althought not all) cases. How you improve this I don't know, although you might be able to nibble around the edges by improving the ability of people to just sit around and tinker with "dumb" (by the judgment of committees) ideas, since it's really only ideas considered at the time by the majority to be "dumb" that can turn out (in hindsight) to have been brilliant.
I can think of an avenue that isn't mentioned here but that I'd consider pretty damn important: academia is a horrid place to work at. Researchers have little choice in what they study (and I'd argue that most of the greatest advancements came from people obsessed with their field of study, whose research was guided by interest and their own ideas, not primarily where they'd find an underpaid job). Wages are laughably low. Job security is basically nonexistent unless you get tenure. If driven, intelligent, ambitious people don't get a chance to pursue their ideas, then they likely won't make the breakthrough they are capable of, and very few people really get that chance.
Anecdote: a friend of my mother's defended her thesis while undergoing chemotherapy, and lived apart from her husband and daughter for a decade because their careers were impossible to consolidate in a single city. She's a professor now, but nobody should have to go through that to have a shot at this.
How many people give up on research because of life circumstances? Not wanting to sacrifice their family, or sanity, for meager pay?
Then there's the ruthless pressure to publish, tweak data, the time spent writing grant applications etc, and the incentives that lead to large numbers of basically worthless papers, studies done on twenty college students and the like. Many of the people writing those want to do real research, but can't.
I don't have a solution here, but if we could aim the existing brainpower better (by which I mean, aim it less, because self-aimed talent is always more effective than people forced to work on stuff they're not passionate about) that might lead to more advances than increasing that brain power, or doubling the number of people possessing it.
All this (to the extent it holds) applies to fundamental science. On the margin, would additional researchers have more benefit in fundamental science (which is mostly done in academia) or at applied science (which is mostly done at private companies)?
Somebody wrote that quite some breakthroughs of past centuries were done by English clergy who had comfortable and safe living conditions, good education and enough time on their hands to pursuit whatever they liked. They had no hightech labs of course.
It's something of an argument for UBI.
Pre-singularity UBI is probably going to be too diffuse for this; you need concentrations of wealth among smart well-educated wannabe researchers. And it works better if those people can hire lab techs, for which you need people who need jobs (or at least strongly benefit from jobs, which is hard to square with a UBI generous enough to buy lab equipment).
I assume that UBI gives people slack for crowd-funding and institutions, so at least small research projects involving multiple people should happen.
Those English clergy-- did them having real but not onerous day jobs do them any good?
UBI also relates to the argument from Bret Weinstein and Heather Heyer that universities are biased towards expensive research that they can take a cut of, and there isn't enough theoretical work getting funded.
I think most of your points land but for some well-researched pushback, have a look at Alexey Guzey's piece (specific to life sciences) - https://guzey.com/how-life-sciences-actually-work/
That was a great read, thank you very much, though it doesn't come away saying "everything's fine", rather "It's shit, but it still works, somehow." Life (science), uh, finds a way.
I suspect that there's some overlap with the issue of hiring competent managers. Most bosses suck at bossing - you'd think this is something the market could figure out, but it doesn't. Maybe you could even link it to politicians. The underlying common problem is one of selection of leaders/elites and of effective allocation of limited resources, and market failures seem to be the norm, as well as failures of pretty much every other mechanism we know of. I expect smarter people than me have tried to tackle this, so I have nothing to contribute at this point.
> Selecting for intelligence feels likely to be banned
Quite possibly it will be in some jurisdictions. But if not all jurisdictions ban it, then there are going to be early adopters who want to do it, and once a significant number do, a lot of other people are going to want to, to keep up. There's also the point that if you have the raw data, they can't ban it.
Having said that, +3 IQ points is not a great deal, and for most prospective parents they could get a bigger boost than that with sperm/egg donation. Some people wouldn't want that, but others would.
You say that other people are going to want to select for intelligence to keep up with the others, but how many IVF babies are there going to be to keep up with, realistically? 1-2% of annual US births are IVF, and unless something happens to drastically increase that number, I don't see how adding 3 IQ points to 1-2% of the population (at most) is a compelling reason to unban a practice people consider unethical.
Adding 3 IQ points to the entire population may be easily worth the cost of conceiving every baby through IVF. IVF can have some complications, but they don't seem particularly serious or unsolvable. (You say "unban", but is it currently banned?)
I don't necessarily disagree that conceiving every baby through IVF would be a net positive, but how do you see that happening? I can't imagine how much it would cost to scale up IVF facilities and staff 100-fold, let alone the costs of actually operating them at that scale. Is that really worth the cost? It seems exceedingly unlikely that there aren't better ways to spend that money for the same, or more, benefit.
Things usually cost less, not more, when scaled up. (They might cost more if we are hitting resource limits, but that's unlikely to be a factor for IVF.) Assuming a generous $20,000 for the cost of IVF and genetic selection, it easily pays for itself through the lifetime of the child, even with modest assumptions about the correlation between intelligence and income. And that's not even accounting for the knock-on effects (such as smart people providing greater economic surplus to others in addition to making more money themselves, or a smarter society making better political decisions).
Who is paying thhose $20k? Many people can not afford that
In a world where you can select for intelligence, you can likely select for a number of other health/well being factors as well. Anyone with the financial means to do so would then face pressure to use IVF, and a scale up could realistically happen I think.
That world is a ways away, if it ever arrives, but I don't think its outside the realm of real possibility.
Can we acknowledge somewhere that for all this IVF you need an awful lot of women who could conceive naturally to consent to it? I wouldn’t have put myself through that to raise my kid’s IQ by three points. Maybe if I had a sufficiently horrible disease running in my family, but the assumed chance of various common diseases we do tend to get wouldn’t have prompted me to do IVF just so I could do polygenic screening.
A +3 IQ points increase across the population would be a big deal, easily a bigger deal than all issues at stake at a typical election combined.
+3 IQ points is a bigger boost in cognitive ability for someone starting from a higher base. I suspect the boost is not uniform -- there are only so many SNPs you can optimize, and smarter folks are already closer to the optimal setting.
But thinking about IQ makes this boost seem zero-sum -- after all, the number itself is relative to the population, not an absolute measure of cognitive ability, i.e., not everyone can "win" in this IQ boosting game. But suppose there was some score for the aggregate effect of those SNPs. Then we'll have an absolute measure for how much headroom we all have (how far do we have before we've optimized all the SNPs?); perhaps all of us, including the smarter ones, are laughably far away from this human ideal. But against this absolute measure (and not a relative measure like IQ is) everyone can (in principle) win, and the ultimate victory condition for the human race is that everyone has maxed out their SNP score, and everyone starts from a level playing field.
If we imagine someone like von Neumann was probably one of the most genetically and environmentally intelligent people, it's conceivable we could all reach around what von Neumann has but due to pleiotropy, I imagine we would start being like him in other ways. I would guess that any living human being is no where near maxing out their PGS for intelligence so we could go well beyond von Neumann, Einstein and so forth. But I think it would take time and have to come at a cost of changes to other aspects of ones being.
>Selecting for intelligence feels likely to be banned
Fuck, does that mean I need to go all the way over to a uncucked country?
Banning it would be an enormous tragedy for humanity.
>Selecting for intelligence feels likely to be banned
Does not feel likely to me.
The 'don't discriminate against/devalue people with low IQ' argument is something that gets heard a lot by people who fetishize IQ (us), because they represent the natural opponent 'side' to the type of person who would make the argument, and the social media ecosystem is efficient at throwing people into their natural opponents to produce content.
But I don't think any of this is something the average person thinks about, and I think the average person is pretty positive on the idea of IQ=good. I don't think it would occur to enough normal people that this might be something you would want to ban, certainly not enough to result in regulation.
Well in the US maybe. But some other country will allow it and own the world in a generation or two, and everyone in the US will [still] be angry and miserable.
"this could be hugely beneficial for humanity if widespread" why?
If they're doing the whole thing for $1400, then they're not doing full sequencing on all the embryos (unless there have been some huge breakthroughs which I missed). They're probably using rna microprobes like 23&me does. This means the ability to select for traits they didn't have in mind will be limited.
So how much would it cost to sequence a whole genome? And what's the likelihood of the price going down?
Weirdly enough, some companies are claiming prices below $1000:
https://www.cnbc.com/2019/07/01/for-600-veritas-genetics-sequences-6point4-billion-letters-of-your-dna.html
But you'd have to do it for all the embryo candidates, right? So, if we take the price of $600 from the article, that's $6,000 for 10 embryos.
Scott did say it is $1400 per embryo in the article.
He said the cost was $1400, plus some extra per embryo (so the per-embryo cost is lower than that).
No, they're certainly not sequencing the entire genome. They're just doing the same old looking for SNP fingerprints. That is presumably why the results are so poor.
Full sequencing is now much cheaper than $1400. Nebula Genomics is doing it right now for $499, Dante Labs runs yearly sales offering it for 300 euros etc., the price has really come down a lot in the last 2-3 years.
It's down to $299 for accurate full-genome sequencing at Nebula. So assuming it's $1400 + $300 per embryo, one cycle of 10 embryos will cost $12k for the basic IVF + $300*10 + $1400 = $16400
What's the value of an IQ point? In terms of income it's probably about $1500/year for adults, based on eyeballing these graphs: (https://pumpkinperson.com/2016/02/11/the-incredible-correlation-between-iq-income/)
It's not linear so it sort of depends on where you are in the distribution. I'm assuming the average IVF-user will be around 115.
Assuming that $1500/year keeps up with inflation, and our discount rate equals the 30 year treasury rate equals the long term average rate of inflation, we can just multiply $1500 by about 40 years of working to get $60,000 as the value of one IQ point.
If instead your discount rate is 4% above inflation (a reasonable forward estimate of the expected return of SPY, which is below historical averages but justified by the abnormally high PE ratio presently) and the income starts 25 years after the IVF, then the value of an IQ point comes down to about $11k, and it's still worth it to get 3 points for $15200.
But assuming the $1500/year only keeps up with inflation is too pessimistic -- it should track overall income growth, which should be 2% faster than inflation. If SPY is 4% above inflation but only 2% above income growth, we use a 2% discount rate on the $1500/year annuity from 2045-2084 to get a present value of $25k.
25k is a lower bound on the value of one IQ point because it only considers the effect on individual income and not any of the other benefits of having higher IQ, such as better health and positive externalities on the community (through better science, better businesses, better political institutions, lower crime).
Getting 3 IQ points with a present value of at least 3x25k for only $16400 is an excellent deal.
The government taxes an average of 29% of people's incomes (https://www.thebalance.com/what-the-average-american-pays-in-taxes-4768594), so from the government's point of view it should be very worth it to pay $16400 now for 29% of $75,000 worth of future earnings. And arguably the government should use a lower discount rate than individuals because its opportunity cost is paying off 30 year treasuries yielding 2% instead of buying SPY yielding 6%. 29% of 3x60k is $52k of present value of future tax revenue that the government could get from paying $16400 for the whole package of IVF and embryo selection. (Before even counting the government's reduced healthcare costs due to the disease screening part).
I think that's probably not the full cost for this purpose.
(disclaimer - I've done some genome sequencing, but only of bacteria.)
The $299 nebula deal is for 30-fold coverage - that's an average, so some regions may be missing. I can't see which sequencing technology they're using, which affects what how much coverage you'd want, and also what sort of artifacts you'd expect to see. All these human sequencing packages only work because there's a good reference, so you might end up with reference sequence replacing a difference they couldn't get a good read of.
That only matters if that region actually differs, and you'll still catch most mutations I imagine. If you care about which alleles are together on the same chromosome, you'd really want to be using a long read technology. Using different chemistries together is good to get better sequences, but I doubt they're doing that.
Don't get me wrong, it's certainly impressive. Given that it's discounted from $1000, it's possible this price is a loss-leader using investor money to build the business, or something. But for the sake of argument, let's suppose not.
However, there's also the issue that an embryo isn't very many cells. You can afford to pinch a few for testing, but for a near-complete sequence you want at least many.
I'm not clear on how much saliva Nebula needs for that service, but it might be ... quite a lot of DNA. I found these statements on the web:
* "The median yield of DNA from a 2 ml saliva sample using Oragene is 110 µg", and
* "How much DNA does a human cell contain? A human cell contains about 6 pg of DNA.", and
* "DNA Sample Submission- Typically 100 to 1000 nanograms of DNA are required for whole genome or whole exome sequencing."
So realistically you probably want to aim for at least something like 200 pg of DNA as an input, or about 33 cells-worth - this ignores all losses in purification.
(You might think that 30 cells would be the minimum /anyway/, if you're getting 30-fold coverage. That's not necessarily the case, but if not it's probably also not complete coverage; you'd be sequencing some molecules multiple times and others none.) Anyway, I imagine these companies are using significantly more starting material than that.
So either you need to grow the cells up, or clone the DNA. Starting with one or two cells, the latter approach would probably give artifacts (missing sections, over-copied sections, sequence changes). If you care very much about the differences, you're going to have to go with the first option - which is going to cost more.
Aren't you assuming the IQ points are a certainty for the cost invested? That is, the investment is risk-free? But biology doesn't work that way. You're investing $15,000 for a certain probability distribution of outcomes with a mean of +3 IQ points. But there is certainly a range of outcomes, and what is the width of that distribution? If it's wide enough it's a pretty risky investment, since the odds are not bad that you get zip for your $$, and don't you need to do some discounting because of the increased risk?
I woudn't think so unless the value of the tails of the distribution is asymmetrical. For early adopters of this technology, I would actually expect it to work in the opposite direction: since the marginal benefit of one additional IQ point is steepest at the tails, and since the average early adopter of IVF is likely to be somewhat above average, the high tail of the distribution is likely to have more positive value than the lower tail, which is closer to average.
To be clear, does a couple doing this with a donor take up additional eggs that could have gone to somebody else, or does it use as many as "traditional" ivf? Neither this post nor the first linked article specified
Generally speaking intended parents will purchase an entire cycle’s worth of eggs from a donor and get the number they get. There are companies that pre-harvest the eggs and sell them one by one but it’s less common.
>Are these tribes based on geography? Are they based on race, ethnic origin, religion, IQ, what TV channels you watched as a kid? I don’t know.
>Some of it is certainly genetic – estimates of the genetic contribution to political association range from 0.4 to 0.6. Heritability of one’s attitudes toward gay rights range from 0.3 to 0.5, which hilariously is a little more heritable than homosexuality itself.
>(for an interesting attempt to break these down into more rigorous concepts like “traditionalism”, “authoritarianism”, and “in-group favoritism” and find the genetic loading for each see here. For an attempt to trace the specific genes involved, which mostly turn out to be NMDA receptors, see here)
(https://slatestarcodex.com/2014/09/30/i-can-tolerate-anything-except-the-outgroup/)
I can think of a few governments that might want to select babies for personality, so that citizens are compliant and non-rebellious. And i can think of a few political-moral points of view that might also want to select babies on personality, so as to get future people more likely to agree with their point of view.
The big limiter here is "if you're doing IVF anyway." I doubt anyone would opt for IVF just for the benefit of genetic selection, and I don't think medical providers do the procedure unless natural conception is unsuccessful or inadvisable.
I can see this shifting more and more over time though, if IVF becomes the ‘safest’ thing to do wrt genetic deseases.
What about a negative feedback effect? The more IVF is used to eliminate genetic risk factors, the fewer future generations have need of IVF.
Not necessarily. If you implant the embryo that has 1 copy of the cyctic fibrosis allele, the baby will be fine but your grandkids are still at risk.
That could happen, but I think it would be many generations away. Unless almost the entire population was screened this way it would take an awful long time for genetic selection to weed this out, assuming people continue to intermarry between classes of non-IVF/IVF born humans.
Maybe far in the future, after all genetic risk factors are removed from the gene pool. But it seems unlikely to me that we'd abandon this practice after using it extensively enough to eliminate genetic risk factors, because:
1. There are always random chromosomal mutations that you might want to screen for.
2. If we get accustomed to "picking the best embryo", then we might get used to all the benefits to be had from selecting the best combination of the parents' genes, rather than just removing any actively-bad genetic risk factors. (Selecting for the highest-IQ combination being one obvious example.)
I totally would. And although I am not judging others I personally feel morally responsible to do so.
The marginal benefit is very small compared to intentionally selecting a mate for good genetics, or if you have a history of disease in your own family, not breeding at all.
Other complicating factor is the marginal benefit depends on where you sit on the margin. If you have very healthy genes already, you get a lot less out of this than someone who doesn't.
And, obviously, if you're not a woman, this isn't your choice anyway.
after some point this process will go from obscure to mainstream, and then it will be something parents desperately want to do, along the lines of getting accepted to the best pre-K daycare and enrolling kids in college-prep classes in middle school.
I would. There is an history of mental illness in my family. If IVF is the only way to seriously reduce risk, I'll go with it. The current plan is to not have any, since I don't wish the hell that can be on my children. I get why people would think that weird but I would be unable to look at my child face if there were any way to avoid a depressing disability that I didn't do.
IVF is usually out of pocket. I don’t see why it would be restricted.
My wife's brother is an institutionalized schizophrenic. If this had been a reasonable option when we were having our kids, I would have gone for it 10 out of 10 times. Schizophrenia is scary as hell.
How exactly is this "relative risk reduction" measured ? They say it is "extrapolated from empirical data", but I don't know what that means.
If they mean, "we implanted N embryos, half screened using our algorithm and half at random, and the screened ones had X% less prevalence of genetic diseases in real life", then I might be mildly interested. On the other hand, if they mean, "we obtained a bunch of markers from GWAS, screened all the embryos for them, and assigned a score to each embryo based on its alleles", then I'm almost completely uninterested, because human traits (outside of a few outliers) are so polygenic that you can basically calculate whatever result you want based on how you tweak your model parameters.
One way to verify it would be the following: You sequence the genome of many pairs of siblings where one got some disease and the other didn't. You use the data from only half of the pairs to construct your algorithm. Then you apply the algorithm to the other half of the pairs, and look at how often it would have picked the one who didn't get the disease.
I don't know what they actually did. It's certainly not "we implanted N embryos, half screened using our algorithm and half at random, and the screened ones had X% less prevalence of genetic diseases in real life", because that would require them to actually implant the embryos decades ago.
Yes, I understand that you're talking about training your model and then cross-validating it. The predictive value of such a process is not zero, by any means; still, based on what I've seen from GWAS before, I doubt its effectiveness in practice.
Unfortunately, we can't possibly know if this works until many more polygenically screen babies are born, then wait 70 years to see if they really live full lives with lower rates of the indicated diseases than regular babies born to the same parents. That will likely never be possible because parents won't randomly select only some babies for screening, so we'll be left with the next best comparison to babies from other parents.
As I described in the sibling comment, and Steve Hsu has also described below, we *can* possibly know if it works by sequencing the genome of pairs of siblings who are now old, and looking at whether the method would have picked the healthier one.
You can possibly know if polygenic screening in general could work. I'm saying you can only know if one specific company's product works by actually testing the results of that product.
Time to start campaigning to get lots of IVF parents to have two kids, do polygenic screening on both, but then the lab randomly selects one of the two to ignore the parents' selection and pick an embryo at random instead (this is the control group)
Aurea means "golden" in Latin. Dawn is "aurora."
Also I'm picturing every yuppie mum hiring a lawyer for when Mike isn't 6' and Suzy isn't smart in 20 years and I hope it's entertaining
The entertainment value is diluted for me by the prospect of another bonaza for lawyers - 'Is your child dumber than you bargained for?'
Think of the targeted advertising though!!! And the intricate legal arguments for like the inclusion of a kibra variant that gives you near eidetic memory but also makes it that much easier to develop PTSD
Although given how easy it is to use patented technology that's technically different but functionally/biologically not because law is so far behind on understanding biology, I'm sure the parents won't win? On the other hand Erin Brokovich sometimes happens when irl she would have had an actual scientific case doing like neuroblastoma rates in Rockford Illinois where furniture manufacturing first took off
I am thinking that now, and thanking God (or rationalist equivalent higher power) we already have 3 passably functional kids and not in the market for any more 😉
The entertainment value is diluted for me by imagining the way parents will treat children who are so disappointing. There's enough abuse already without adding genetic engineering to the mix.
Is there a genetic basis for being emotionally abusive? Would anyone sign up for it being edited out of their children?
I'm sure that the companies will be very careful not to promise too much, for exactly this reason. I doubt you can sue them if you get cancer or a rare genetic disease, for example.
In extremely related news, the lobster genome is out and it's so fascinating!!! https://advances.sciencemag.org/content/7/26/eabe8290
Any insights into lobster hierarchies and room cleaning?
Hail Lobster.
What a coincidence; recently got contacted by some lobster uploads looking to escape their Russian research facility. Small world!
Aurea looks somewhat shocked - could it be...
a) her parents have just told her she's the first polygenically screened baby
b) she just read the label on her bedding(?) which seems to be about suffocating infants, or
c) she can't believe Scott thinks Aurea means "dawn" when she thought it meant "golden" (gotta update them priors baby 😉)
Vote now!
I vote D she just pooped her pants.
I swear babies poop their pants more often than they say gaga
Scott also asked whether or not a name is coincidence, so perhaps he is just unwell.
B. Even a very bright designer baby, apparently capable of reading weeks after birth, won't have lived long enough to understand that those labels correspond to extremely low absolute risks.
Poor baby probably thinks all babies are killed by consumer products by the age of 2.
I saw a search result that stated that 'dawn' is _one_ of the meanings of 'aurea' and results with other unrelated meanings as well, so I'm not so sure that 'aurea' as 'dawn' is definitely wrong, especially given both the way language works in general and that there are lots of languages (and dialects) based on the supposed origin language of the term (Latin).
And 'golden dawn' is a pretty common phrase too, 'aurea' seems (based on my cursory skim of search results for "aurea") based on Aurora anyways (which was the goddess of the dawn), so ... I'll give Scott a pass on this 'mistake'!
It just makes me think of Staph A. Which is unfortunate.
The adjective 'aureus' means something closer to 'the light of day,' which itself is golden - alternatively, it could mean something like shining, excellent, etc. (the etymology being derived from 'aurum')
Dawn, as in the morning/daybreak, is always aurora. It gets confusing when you factor in the unrelated 'aura -ae,' since this has a Virgilian connection with the heavens and daylight, versus the darkness of the underworld.
I am concerned that we do not understand this well enough. What if, for instance, we find that genes that correlate with disease also correlate with some particular emotion? Or that (the genes we believe increase) intelligence are inversely correlated with empathy? Under a host of horrific hypotheticals, widespread adoption could be catastrophic, creating an entire generation that is missing an attribute, has far different statistical outcomes from the norm, etc. I leave it to those with more imagination than myself to generate better scenarios, and those with more knowledge to figure out if they could actually happen.
This makes Heinlein's Methuselah Project look like it belongs in a high school science fair. This is strong medicine. It will be applied exclusively by the ignorant (since that's all of us, right now) and, also, mostly by idiots who haven't thought about what they are doing.
I strongly suspect it will be done, at least in some if not many places, and I believe the impact will be large. I do not know if it will be positive or negative - or, more likely, both.
"For He knows what we are made of, and that it is dust." But perhaps not for much longer.
Chin up. Biochemistry is so unbelievably stuffed with redundancy it seems very unlikely to me to be anything more impactful than the cloning of Dolly the sheep, which was going to usher in a Brave New World of cloning in about 8 months flat, 25 years ago now. If it were *possible* to routinely pick out 1 out of 10 IVF embryos that would end up very different from its parents -- 2x smarter, wholly free of disease, able to leap buildings in a single bound -- then this kind of thing would happen out in the wild in 10% of natural births already -- and that is not what we see. Children generally end up pretty similar to their parents, and wild deviations, where a genius is born from IQ 105 parents, say, are exceedingly rare, 1 out of 10 million kind of events. So yeah if you could screen 10 million embryos, you might pick out the one rara avis and get results that would make the Howard Foundation proud.
It's literally just embryo selection. Genetic counselors have been informally doing this for a while. They're not interfering or engineering in any way- like editing blastocysts with strong promoters around magic machiavellian genes to ensure psycho hitler.
Like we are literally closer to Jurassic Park being a reality than your vision of human genetics - https://pleistocenepark.ru
In case you have forgotten:
- the literal Adolf Hitler was conceived naturally
- psychopaths are conceived naturally every day
- a small percentage of people are willing to defy norms and start respectability cascades
It is possible to set everything on fire with only quantitative changes.
That said, there are some obvious bounds here. If a trait has frequency X0 in the population, this form of selection is taken up at frequency Y, and the average number of embryos selected from is Z, then the frequency of the trait X1 after one generation is bounded by:
(1-Y)*X0 + Y*X0^Z < X1 < (1-Y)*X0 + Y*(1-(1-X0)^Z)
Yeah, this is right. In particular (1) I bet those graphs reflect prediction from pooled population samples, not causality estimated from sibling groups and leveraging the "lottery of meiosis". In which case, embryo selection may be less effective than predicted, maybe even have zero effect in some cases. But also (2) we have no idea what all these genes actually do, we've got no idea about the biological pathways between them and the outcome, we've got no idea of possible side effects. Basically, this might be about as irresponsible as handing out an untested drug.
But, but, we could eliminate obesity! And everyone would be tall!
And when everyone's tall.... no-one will be *evil laughter*
If you're only selecting among ten possible embryos, you can only move your kid into the 90th %ile or the 10th %ile.
The specific method described above is merely the tip of an iceberg.
Fortunately IVF is extremely expensive and unpleasant, so we'll have a very small number of test cases to look at long before the technology becoming ubiquitous is an option.
If there's some innate problems with these techniques, we'll have a chance to see it before it affects the general population, and adjust.
This is a valid concern. It is possible that if we selected strongly enough for trait X, it could decrease (or increase for that matter) trait Y in a way we don't like.
But there are three reasons I don't think this is going to be much of a problem in the next 50 years.
1) The strongest negative correlation between two disease traits we know of is the correlation of kidney disease and ulcerative collitis, at -0.3. Most traits seem to be mostly independent of one another.
2) We don't have that much selective power right now. There are two limiting factors for embryo selection: the number of embryos you have to work with and the percentage of variance in the trait that you can explain with genetic testing. Even with a really good genetic test (which we don't really have right now), and a lot of embryos (like 30 if you start egg freezing early), you'd still only be able to get about +/-1 standard deviation on any given trait.
3) We can largely mitigate this possibility by selecing on multiple traits. If we're worried that selecting against lung cancer risk may accidentally select for genes that make you die before you can develop lung cancer we can introduce a test for healthy lifespan.
4) There are many tradeoffs that humans made in their evolutionary past that are clearly not well selected for the modern world. For example, humans have very short lifespans given their low rates of all-cause mortality. If there is a gene that makes you likely to reproduce younger but kills you at an old age, that gene will be selected for in environments with high all-cause mortality. If you are likely to die anyways from some random unavoidable cause, evolution would much rather you reproduce before then. Modern humans have something like 1/10th the death rate of hunter-gatherers at ages before 50. So even if we're doing what evolution does and optimizing for inclusive reproductive fitness, we STILL would have a lot of fertile ground to explore just by taking the obvious steps to decrease disease rates.
Re 1) - there is a stronger negative correlation; congenital total blindness + schizophrenia has never been found. Of course, essentially everyone would pick "possibility of schizophrenia" over "blind", so this is not really a notable tradeoff.
Re 3) - there are a couple of sticky cases. One is where legible trait A is correlated in a tradeoff with illegible trait B, but because B is illegible you don't (yet) know about the correlation. The other is the "mean chickens" problem: some of the obvious criteria to optimise on, like income, may actually optimise for greed rather than productivity (like how "hen in the shed with the highest egg production" optimises for the hen that pecks the other hens to make them too sick to lay, or "beetle group with the lowest population" optimises for beetles that breed like crazy but then eat *other* beetles' babies, or how democracy optimises for demagoguery more strongly than it optimises for good governance, or how Enron's attempt to use evolution by firing the "least productive 10%" of workers optimised for cheating on the metrics).
Interesting point about schizophrenia and blindness. I didn't know. My comment was based on data from LDHub, but I guess they don't track schizophrenia + blindness?
You're right about the issue with illegible traits of course. I think that is one of the biggest potential risks with embryo selection (though I don't think it is likely to become an issue until we start to push substantially beyond the tails of traits in existing humans). Evolution deals with this issue by trying everything all the time and letting its mistakes kill or cripple organisms. It's a pretty brutal system, but it "works" in the sense that it generally leads to fitter species over time.
But I don't think such a brutal system is actually necessary. Evolution is in some sense the dumbest possible algorithm for creating complex systems. The miracle is not that it works so well, but that it works at all.
Here's the article Scott linked ages ago on blindness vs. schizophrenia: https://mindhacks.com/2014/11/15/more-on-the-enigma-of-blindness-and-psychosis/
Somewhat skeptical of the efficacy of all this when most of the data comes from the company itself. How strictly is something like this regulated? Is there any way to verify that when they for example that there's a 60% lower chance of cancer that the math they're using adds up?
> Is there any way to verify that when they for example that there's a 60% lower chance of cancer that the math they're using adds up?
Yes. None of these companies are big enough to fund their own genetics studies yet, so all the predictors come from open-source databases like this one: https://www.ebi.ac.uk/gwas/home
Furthermore, most of them public their predictors in articles you can find on SciHub, so you can see the set of SNPs they use to contruct the predictors. It might be hard to replicate their findings yourself, but there are very often studies from unaffiliated scientists that have predictors capable of explaining a similar level of variance.
The math to calculate expected reduction given parental polygenic risk scores, number of embryos and disease prevalence is not controversial. It's pretty standard order statistics on normal distributions. The only real question is what percentage of variance their predictors can explain, which is where seeing that other researchers have constructed predictors with similar levels of explanatory power is reassuring (or not, depending on what you find).
Here's a new article in the New England Journal of Medicine:
Problems with Using Polygenic Scores to Select Embryos
https://www.nejm.org/doi/full/10.1056/NEJMsr2105065
Here is the full article: https://www.dropbox.com/s/l1gklud7udot4jj/nejmsr2105065.pdf
On one hand the article seems to suggest that this technology is not very effective. On the other hand it expresses concerns about exacerbating inequalities. I feel like at most one of these two concerns can be valid; not both at the same time.
There is a section "unintended consequences" which says that selecting for high IQ would also increase the risk of bipolar disorder. What's not mentioned is that selecting for high IQ would decrease the risk of most other diseases. Bipolar disorder is an exception in that regard. Genetically, most good things cluster together with other good things. So most unintended consequences would actually be positive.
It's worth keeping in mind that most scientists have career goals in mind, and that an article endorsing these technologies might currently not advance these goals as much as an article which is critical of them.
Thanks for sharing this. A couple of months ago I wrote this Metaculus question on the same topic: https://www.metaculus.com/questions/7031/first-commercial-polygenic-embryo-screening/ I did it under the assumption that Orchid Health would be the first to come to market with PGS screening. Seems like I missed this kid!
David Plotz wrote a book about the much derided Nobel Prize sperm bank in 2005 by interviewing the children. He was impressed by the offspring, who struck him as on average intelligent and thoughtful (at least the ones who felt like engaging with the man from Slate).
On the other hand, with well over a million children in the US having been conceived via sperm or egg donations, I've never noticed any large scale social effects from the purchasing of selected gametes.
For example, I presume that lesbians, as in the movie "The Kids Are Alright," are much more likely than heterosexuals to have children whose biological fathers were selected from sperm bank catalogs. Do lesbians therefore tend to have super children? I don't know. I've never heard that they do, but maybe they do. Has anybody ever heard of a study?
I used to follow whom lesbian celebrities used as their sperm donors: generally, other celebrities.
A sad story: Back in ~2000 I thought it unwise of singer Melissa Etheridge to use noted substance abuser CSN&Y singer David Crosby as a sperm donor even though he'd just gotten a liver transplant.
Last year, their child died:
https://www.yahoo.com/now/melissa-etheridges-son-beckett-dies-david-crosby-says-its-not-true-that-he-was-just-a-donor-145316589.html
Granted, "it seems likely to me" is a weak statement, but it seems likely to me things like selecting donors from sperm banks and even polygenic screening can't make much of a difference compared to existing assortative mating practices. The women for whom having that kind of choice might matter can't afford it anyway. You're left with some tiny segment of women sufficiently affluent and living in the right place, but somehow extremely unattractive anyway.
Which is to say the hetero women in the same social class as the lesbians taking their pick from sperm banks are just marrying the sperm bank donors.
Something interesting to see would be adoption of practices like this to breed super-athletes, though. Given how common lesbians are in the ranks of extremely elite female athletes, we're arguably missing out on being able to do things like breed Kobe Bryant with Diana Taurasi. Taurasi never did reveal who her donor actually was.
My impression is that lesbians can also choose to get sperm from a male friend. That would involve fewer options, but is cheaper. I would also assume they'd chose a friend who doesn't have obvious genetic problems.
This would obfuscate whatever effects there are from IVF.
That is a very cute baby.
Glad you think so, because we'll all be her slave someday.
Here's some background on the validation of polygenic risk scores, pleiotropy, etc.
The effectiveness of polygenic disease risk predictors is tested using tens of thousands of siblings for whom we have genotypes and medical history (they are typically 50-70 years old). We specifically test how well the predictor can pick out a sibling with the condition from a pair:
"Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc."
Risk reduction has been validated using sib data in several independent studies.
Sibling validation of polygenic risk scores and complex trait prediction
https://www.nature.com/articles/s41598-020-69927-7
We test 26 polygenic predictors using tens of thousands of genetic siblings from the UK Biobank (UKB), for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in between-sibling designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. 55–65% of the time the higher PRS sibling is the case. For quantitative traits such as height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.
See also this 2021 review article, to appear in "Genomic Prediction of Complex Traits", Springer Nature book series "Methods in Molecular Biology"
Among other things it discusses pleiotropy and the genetic architecture of disease risks. DNA regions used to predict different risks are largely disjoint. Selection on a risk index (e.g., 10 conditions) has been shown (using sib data) to deliver average risk reduction for all of the diseases in the index.
https://arxiv.org/abs/2101.05870
What is known about the long-term health effects of IVF? My understanding is that people born through IVF are pretty normal as far as we can tell, but the oldest person born through IVF is now 42 so there are possible long-term effects for which we just can't tell. I want to point out the risk that if IVF embryo selection becomes really effective people will start using IVF when not medically necessary, and will eventually suffer long-term health effects that we aren't aware of because nobody with IVF lived that long yet. This risk seems pretty low, though.
You don’t need to reach for unknown long term effects. There’s a statistically significant increase in birth defects.
I don’t think even LifeView would say the benefits outweigh the risks at the present time if polygenetic scoring is the only reason you are considering IVF.
"There’s a statistically significant increase in birth defects."
Is this before or after after controlling for the age of the parents and all their other preexisting conditions? Age and other prexisting conditions would increase both birth defects and the infertility that causes people to seek IVF in the first place.
There’s a debate in the literature. After familiarizing myself with it I was convinced that the effect size is reduced but still exists. Your conclusions may vary.
I think there might be a trend in gametic integrity but definitely fact check.
this sort of thing is probably genetically confounded, because genetics would contribute to the fertility problems that caused their parents to seek IVF.
I would love to see an RCT where a few hundred young healthy fertile couples pre-register and half of them are randomly selected to get IVF with embryo selection.
There are lots of problems with IVF. In natural conception, all the sperm compete to overcome the female fortress of the birth canal to get to the egg. Only one wins. This is a profoundly powerful method of natural selection of the fittest. In IVF, there is no natural competition for the egg. All the sperm are mixed with the egg, and the lucky one wins. This selects for the middle of the probability distribution, i.e. for the average sperm.
Using polygenic scores for IVF starts with an average embryo and then hopes to increase the probability for a marginally higher than average embryo. If IVF were done on a large scale it would have a regressive effect on the human population. See this video by Ed Dutton:
https://www.youtube.com/watch?v=FHZGsiZtjDY
Admittingly this kind of concerns me. Some of our most brilliant people have been clinically flawed in some way (like John Nash, Elon Musk Nicola Tesla) and there's good reason speculate that their "bad genes" correlate with or are the cause of their brilliance. Who knows what geniuses we would be depriving ourselves of?
Yeah, eugenics is a poisoned chalice that I don't think we should be drinking from, and I definitely think this is eugenics.
Is it eugenics when lesbians pore over catalogs from sperm banks?
I actually think they get a pass on outright eugenics with that; sounds more like supercharged selective mating. Not free of problems itself; but; I don't see a slippery slope down from there aside from perhaps single women choosing to do the same rather than settle for someone they feel is beneath them. But, even if everyone did that; you're at worst condemning nearly everyone to live romantically empty lives and preventing 99% of men from reproducing but allowing free competition for those 1% slots; the worst case scenario doesn't involve anyone having to die; though violence rates would likely shoot up amongst men without wives and children to mellow us down, and in that hyper competitive environment. (Ref Johnathan Gotschall's "The Professor in the Cage")
Whereas this polygenic screening if adopted by everyone, results in billions of unique human beings being created, tested, and snuffed out immediately if not found to be the best amongst their dozen or so siblings. And by setting the standard that, having say, Down Syndrome, is certainly reason enough to not bring someone into the world, you make it so very easy to discard the lives of people who are born with Down Syndrome. Imagine a world where "He should have been screened out, but his parents conceived him irresponsibly and didn't get him tested and terminated." was a common reaction to people born with such diseases?
One of these is a far darker outcome. The lesbians can have their sperm bank catalogues; even if I'm never going to reproduce in that world.
No, most people don't think that if it's OK to screen out a disease before birth (or even before conception), then it's OK to kill a person with that disease after being born. Down syndrome is already easily screened out in prenatal testing, but we don't go around killing people with Down syndrome.
I obviously oppose killing those infants as well.
>I don't see a slippery slope down from there aside from perhaps single women choosing to do the same rather than settle for someone they feel is beneath them.
If a man has zero hope of ever getting someone to bear his child consensually (you say 99%), and values leaving offspring above everything else (not a majority, but non-negligible - say 1%), "rape a woman and kidnap her for 9 months so she can't abort" is his highest-utility option. Success rate and penalty are irrelevant, because E(offspring) dominates the calculus and E(offspring|don't do it) = 0.
This is probably not a great thing to incentivise.
Well, that scenario does broadly fit under my "Violence rates would likely shoot up." comment.
True, but here it's a specific perverse incentive rather than the fuzzier general effects of bachelorhood. This scenario is also dire enough that I feel it merits being laid out in full.
> And by setting the standard that, having say, Down Syndrome, is certainly reason enough to not bring someone into the world, you make it so very easy to discard the lives of people who are born with Down Syndrome.
I really don't see how that follows. You're effectively arguing that accepting the legitimacy of abortion "makes it so very easy" to kill babies after they're born if you suddenly change your mind on raising a child. There are so many propositions you'd have to justify to go from one to the otherand you just gloss over them as if they're immaterial. There are plenty of opportunities to make relevant distinctions that would permit one outcome but not the other.
I mean, Ian is actually positing the more ambitious "it will make Aktion T4 seem more attractive" rather than "abortion and infanticide are not so different", but I'm going to have to go in to defend the latter as legitimate.
There are exactly two propositions dividing abortion from infanticide - bodily autonomy (which stops being a justification at birth, but which is largely a fig leaf for reproductive freedom anyway) and threshold of full killing-is-murder personhood (which has to be after birth for infanticide, while it merely has to be after [stage of abortion] for abortion).
There are a *lot* of historical societies that practiced infanticide-by-exposure as a means of population control (and - well, not quite eu*gen*ics, but eu*phen*ics; preventing disability). It is not something foreign to humanity.
Of course, I'm one of the people in the Singerian camp on this i.e. "thus infanticide isn't terrible" as opposed to "thus abortion is terrible". But there really isn't as much of a distinction as you make out.
> I mean, Ian is actually positing the more ambitious "it will make Aktion T4 seem more attractive" rather than "abortion and infanticide are not so different"
That's my point though. Since we don't accept the less ambitious proposition for various meaningful reasons, it's absurd to think that we would accept the more ambitious one and that there are no meaningful distinctions to be found there.
What would we call this? Neonatal gene editing? Prenatal?
There’s no editing. The IVF process already produces multiple viable embryos (or at least those going through it hope so). This is just a way of deciding which one to use.
This already existed for single gene disorders.
Ahhhh, thanks, I'm a dumbass.
The article says 'the test is fully named “preimplantation genetic testing for polygenic disorders”, or PGT-P for short.' I was also thinking something something pre-implantation something
Here's a beautiful article about how maybe we shouldn't eradicate DOWNS -- maybe there's actually a lot of happiness we're missing out on.
https://www.thenewatlantis.com/publications/at-home-with-down-syndrome
Yeah, I was thinking of mentioning how ethical hedonism is super against eradicating Down's.
I'd prefer that article balance the Down's-mother interviews with interviews with the Down's patients themselves - including the ones who have outlived their loving parents. It's possible Down's is a net happiness gain, at least in a rich society, but this deserves a good deal of skepticism.
Yeah, seems more like a "Hey, here's a silver lining I'm going to focus on." which is probably a fairly healthy way of dealing with things.
But on the balance, if we could cure people with down syndrome, it would probably be better in general. But eliminating people with down syndrome before they're born does not equal curing it in people. And living with down syndrome is a lot better than not living.
it's pretty similar, because in this case "eliminating people with down syndrome before they're born" results in a healthy person being born instead (a healthy embryo is picked instead.) So as far as consequentialist outcome is concerned, it's the same as curing it.
"In theory, you're not supposed to use polygenic screening to produce designer babies."
Is that law? The company's policy? Your ethical opinion? Some people's ethical opinion?
a good question.
This is messed up on multiple levels. Besides the obvious ethical considerations of having an entire social system based around meritocracy being gamed by innately increasing merit potential and essentially playing God based on unclear and short sighted principles, this is something exclusively available to very wealthy people having children very late in life. At a base it would accelerate wealth inequality and the entitled position that many silicon valley and finance bros have in regard to virtually every other segment of American society. Must be stopped at all costs.
> this is something exclusively available to very wealthy people having children very late in life
No, it isn't. IVF itself costs something like $10,000–15,000, and genetic selection is a couple thousand on top of that.
> At a base it would accelerate wealth inequality and the entitled position that many silicon valley and finance bros have in regard to virtually every other segment of American society.
Inequality isn't a problem in and of itself. Poverty is a problem. If inequality increases because the poor are getting poorer, that's a problem. If inequality increases because the rich are getting richer, that's not a problem. Preventing an increase in inequality by banning a procedure that would help the rich get richer but wouldn't make the poor any poorer is terrible tyranny.
I used to feel this way (re: inequality), but it does seem that as a social species (dogs, monkeys, humans, etc.), inequality is itself sufficient to cause social strife. Poor people in the U.S.A. and Western Europe live better than 99% of people historically -- there is almost no real hunger (rather the opposite), there is increasingly a right to shelter, free medical care that, while relatively bad, still far exceeds what anyone had access to pre-modern-medicine.
Additionally, Blacks in the U.S.A. do better than their ethnic peers in sub-saharan Africa; Hispanics than their ethnic peers in South America, etc., but there is still enormous dissatisfaction with inequality.
Conversely, that the chief of some hunter-gatherer tribe -- who has lost 2 of their 6 children during childbirth, who has no expectation of living in their frail elderly years when they cannot walk, is probably quite happy.
IMO if poor people are unhappy solely because others are richer than them, that's their problem, and we shouldn't punish the rich because of that.
Also, in the more reasonable variants of discontent about inequality, people are angry that the wealth of the rich isn't being redistributed to the poor (or, rather, not more of it than currently is). Now, it's questionable if demands to redistribute more wealth are legitimate, or if it can be redistributed without shrinking the pie too much. Nevertheless, the demand is for a policy that would make the rich less rich in a way that at least potentially benefits the poor.
However, keeping the rich from becoming smarter makes the rich less rich in a way that doesn't help the poor in any way. If anything, it reduces the amount of wealth that can be redistributed to the poor.
I generally agree about "The rich getting richer isn't a problem" if "the poor aren't getting poorer" but it does become a problem in at least a couple of areas, most obviously; land. If the rich keep getting richer while the poor stagnate, land prices will rise as the rich compete with each other and the poor become priced out of the land market.
Which is what is happening in North America right now, leading to many people renting and paying money to wealthy landlords instead of owning a property that they can invest their time and labour into.
Hispanic poverty doesn't seem to be nearly the political issue that black poverty is. Presumably their choice to move to the US for a better life is a big part of that.
10,000 to 15,000 expense literally eliminates at least 75% of the country from affording this. IVF is also more like 40-50k nowadays. This is like half of the median take home income of the average American household. America is not SF and NYC. That procedure is effectively considered genocide by like more than half the religious groups in the US.
Half of the *yearly* take home income, or perhaps 1.2% of the lifetime income, for a procedure that (depending on the attributes selected for) may benefit the child for a lifetime. Sure, many people are unwilling to save up a few tens of thousands over a few years, but that doesn't mean that no one but rich people are *able* do it (let alone, as you said, "exclusively very wealthy people", which to me sounds like much less than the top 25%).
Do you have any idea of the microeconomics of the average American household where total liquid savings is something like $700?
Like there are virtually zero banks that will underwrite this loan and at average US savings rates you would be in your late 40s assuming you got married in your mid-20s to afford IVF.
That the average American saves little and has $700 of savings doesn't mean that the average American wouldn't be *able* to save more if they wanted, and have much more savings.
I'm not, as you've insinuated, a rich person from SF or NY. I'm from Hungary, a country where typical salaries are well below those in America, even adjusted for prices. Most Americans, if they were just a little thrifty, should be able to save a large fraction of their salaries.
Well, richer than... most of Africa, the Middle East, India, and Southeast Asia.
Oh, and let's not mention the amount of people who would be categorically opposed to such things due to religious reasons (i.e. the majority of the world).
> Inequality isn't a problem in and of itself. Poverty is a problem.
That's speculative. If human wellness is somewhat predicated on comparative wealth, as it appears to be in some cultures, then large disparities in equality *is* itself a problem.
Stopping human improvement at all costs seems like an extreme position.
Yes, it will almost certainly help the wealthy over the poor. This is true of every human innovation in history, basically. But as with many other innovations, it will likely drift downward to help the poor at some point, especially as society starts to understand that increasing the potential of every citizen is likely to make the whole country/world better off, not just the lives of those who receive the intervention.
There would almost certainly be an intermediate period where inequality rises in some ways, and this could lead to social strife, but I'm confident at least some more conscientious countries would eventually make something like this available to lower classes as it becomes a human rights issue of sorts.
It would also become something of a competitive aspect of foreign affairs. If (insert foreign adversary here) is providing genetic selection to their population, there will be pressure on you to do so also, as they are improving their citizens natural abilities and could outcompete you in industry/military/whatever.
This just sounds like Nazi race science with extra steps instead arguing instead we should use IQ genes as opposed to blond hair and blue eyes.
It's definitely adjacent to it, no question. I wouldn't deny that. But that doesn't mean the idea has no merit at all. It just means we need to think very carefully about what we are doing, why we are doing it, and how, and yes, try to make it as equitable as we can. In my ideal world we remove wealth from the equation entirely, but in our current system that just isn't a possiblity.
It could all end up horribly I suppose, hijacked by racist/prejudiced powers, but it also seems like potentially the best avenue for transcending our current limitations as a species, which are many. The risk vs reward on all of this is unclear, and I could see how many could have a worldview where the risk is too substantial to even contemplate the idea.
But taken on its own as a concept (while granting that removing many things from sociological context makes them appear more attractive), I don't believe there's so much that is objectionable to the idea of improving the odds of an unborn person being more intelligent/kind/whatever trait you could imagine as a societal/individual positive.
I'm all in favor of taking anything like this slowly, with great deliberate thought, and listening to every objection and taking them seriously. Maybe in the end it will be clear that we shouldn't do it, or place extremely restrictive regulation on the entire practice. But to squash it out of fear that it could be exploited without a hard examination of the possible benefits doesn't strike me as the way to go either.
Yeah I'm left with the sense that even if we had tens of generations of strife around this, the next thousand generations would benefit so much that the downsides are trivial
I feel like this is a reductio ad Hitlerum; Nazi eugenics were bad because a) they sucked at race science, b) their eugenics involved mass murder.
This is not a risk-free or drawback-free path to take, but "same plan, but skip the step where you murder ten million people" is actually a rather substantial improvement!
> [Nazi eugenics bad because bad race science and mass murder]
I would like to add forcible sterilization to the list of reasons why Nazi eugenics was bad.
This kind of thinking is why I included the part on genetic engineering at the bottom of https://astralcodexten.substack.com/p/contra-smith-on-jewish-selective
I really think that this is the most promising way to end poverty, inequality, and various social ills, and that banning it would doom billions to terrible lives. And that's even before we get to the civilization-wide benefits like having smart people cure cancer, discover limitless green energy, etc.
Really smart people invented atom bombs and centralized agricultural collectivization and logistics networks to move millions of people to death camps. Really smart people often are just more effective at doing evil than normal people or dumb people and can obfuscate it through several levels of social hierarchy. Intelligence is a good indicator for things like income and social status, but not being a good person, a compassionate person, a caring person, or even a reasonable person. I know plenty of smart people that have reached the heights of their current system who are also insane political extremists who will put their opponents in camps at the first opportunity (on both sides). This is even assuming that the connection between IQ is even that strongly correlated with good outcomes besides the possibility for a bajillion other cofounders.
This is also assuming that we have the complex system that is genetics so thoroughly mapped out that we are not just creating a bunch of Ubermensch like Khan from Star Trek who are really smart and complete sociopathic.
This falls into the neoliberal trap of arguing that there is no need to fix the system, just to enable a purer meritocracy that still maintains all of the trappings of the current system. The most promising route to a better future is just not treating people we consider our economic and social inferiors like shit.
Related: "They do not want progress, they want an advantage" (Bertold Brecht)
I have three questions someone who is familiar can help me with hopefully.
>There are two ways that an egg may be fertilized by IVF: traditional and ICSI. In traditional IVF, 50,000 or more swimming sperm are placed next to the egg in a laboratory dish. Fertilization occurs when one of the sperm enters into the cytoplasm of the egg. In the ICSI process, a tiny needle, called a micropipette, is used to inject a single sperm into the center of the egg. With either traditional IVF or ICSI, once fertilization occurs, the fertilized egg (now called an embryo) grows in a laboratory for 1 to 5 days before it is transferred to the woman’s uterus (womb).[https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/what-is-intracytoplasmic-sperm-injection-icsi/]
1. What effect does directly injecting the sperm have? I assume that swimming to reach the egg and penetrate is a test of fitness. But how much does it matter?
2. If there is a substantial negative effect to directly injecting, would making more and more sperm go through an extremely difficult process before fertilizing select for a healthy sperm that would help make a healthy baby?
3. After enough generations of ICSI, do sperm stop swimming enough to get a woman pregnant? Does IVF cause the need for more IVF?
My wife and I went through a couple of cycles of IVF recently, and actually chatted with Genomic Predictions (the name of Prof Hsu's company beofre it changed to LifeView apparently). For us the big challenge was that the fertility clinic we used to harvest the eggs and then implant the embryo was very limiting in what they would allow us to do in terms of selecting embryos. We were already testing for a (mild) genetic defect I have, and their policy was that if any embryo tested positive for it they would refuse to implant it, in spite of the mild expected impact. (On the other hand if we didn't test for the condition they would accept the 50/50 chance an embryo had it and implant any of our embryos.). When we raised the idea of using something like polygenic risk scoring they shut us down immediately. This is a well known clinic affiliated with a top US hospital, but I looked around a bit and got the sense that it would be a struggle to find a clinic (in the US) that would accept this kind of embryo selection process, although the fact that a baby was born using it suggests maybe this wasn't as much of a challenge as I thought. The solution I considered was finding the egg donor in the US and using our normal clinic to harvest the eggs and create the embryos, then having the genetic testing done, then transferring the embryos to an international clinic more willing to allow us to select the embryo using whatever criteria we wanted.
I guess I'm outing myself as a religious conservative, but you wouldn't have to be a religious conservative to see those embryos that don't get chosen with something like compassion.
Granted, an embryo does not suffer, so the unchosen embryo will not know it never even had a chance. And also granted that many embryos don't survive to birth anyway.
I'm a father of five. One of my daughters is autistic, not too severe, but enough that she'll likely not be able to live independently. I am grateful every day that she's part of the world. My youngest child had markers for Down syndrome while my wife was pregnant with him. While we would have loved and cared for him either way, we were grateful that this turned out to be a false alarm. I like children, and would have wanted more, but five kids is already a lot, so you make your choice.
I'm not sure what my point is, but it's something like this: if life is good (and I think it is), then even a life with some pain or sickness may be a life worth having. I guess I'd like to see some sort of organization established to take all these unchosen embryos, and, at some future date, give them a life and a home somewhere. If my vision of the future is right, I could see many happy, not-quite-perfect children growing up in big, beautiful O'Neill cylinders in the sky.
It is true that all these embtyos are potential lifes that never are, but so is every period a woman has. Are you also founding a center to save them as well? it seems like the value you are trying to maximise for is the amount of happy lifes, however the people doing these tests were always only going to have one child (at least for now) anyway, so this technology makes no difference there.
They are not potential lives: they are lives. I believe you meant to say they are potential people, but to say they are potential lives is scientifically innacurate. The zygote is the first stage of human life, biologically speaking. An egg, as you point out, is a potential life, in that it has the potential to become a human life if it is fertilized. A zygote already is a life, regardless of whether you think it is a life with moral value.
If I told you i have saved 7 lives this week you would feel really impressed until you discover it were those of the floers of my neighbor that weren't getting any water. You would be justified in feeling like you were lied to. Specifically because the context indicated taht i was probably using the definition of life that refered to that of a person or a moral agent. I was using that definition above as well.
But all of this is semantics.
Your comment said that an embryo was a potential life in the same way "every period a woman has" and then asked "Are you also founding a center to save them as well?" Which is a false equivalence that I took umbrage at. It's much more reasonable for someone to feel they have a moral responsibility to an actual human life as opposed to a potential human life.
Late to the discussion, but I wanted to weigh in with this thought. We are coming close to the ability to reliably induce totipotency in previously differentiated cells. What is the line for you in that world? What level of intervention is required to ensure every shed human cell is given the opportunity to develop into a full human being?
This is a misunderstanding of my point: I'm trying to differentiate between potential human lives, and actual human lives from a biological standpoint. A zygote is the earliest stage of human development: it is a human life, not a potential human life. An egg is a potential human life because it has the potential to become a human life under certain circumstances (being fertilized). Human cells generally do not have the potential to become a human life and thus are not potential human lives. If we do develop the ability to induce totipotency in differentiated cells then all that changes is the types of cells which are potential human lives. A skin cell currently cannot become a human life, and thus is not a potential human life: once we have totipotency technology it could become a human life under the right conditions (someone intervening to make it totipotent in such a way as to become a new human life). It thus raises the status of skin cells to be equal to egg cells, not equal to zygotes.
So your line is if the development into a fully grown human can happen naturally or requires technological intervention? But I fail to see how this meaningfully differentiates between an embryo in a petri dish and a somatic cell in the same dish that is one experiment away from totipotency. The two cells have (roughly) the same contents, the same DNA, and only are fundamentally distinguished by which transcription factors are bound to which genes at that moment. I'm oversimplifying to be fair, but it still seems like a rather arbitrary line to me.
It's not my line: it's the biological line. Human life begins with the zygote: that is the earliest stage of biological development for a human. It doesn't begin with an egg, or with a sperm, or with a skin cell, it begins with a zygote. This isn't controversial (see https://en.wikipedia.org/wiki/Development_of_the_human_body , or https://bio.libretexts.org/Bookshelves/Human_Biology/Book%3A_Human_Biology_(Wakim_and_Grewal)/23%3A_Human_Growth_and_Development). A fertilized egg is a human life: a human life at the earliest stage of development, but a human life nonetheless. Presumably if you could induce totipotentality into a human cell then you would in effect be creating a zygote without the use of an egg, but it doesn't change the fact that you would have just created a new human life that is now at it's earliest stage of development.
I'm not here to argue about whether zygotes have rights, I'm here to be a pedant who doesn't like it when people confuse potential human life with actual human life in their arguments. If you have a problem with my definition then take it up with the biologists.
Unlike embryos, periods are not human lives. What would "saving periods" even mean? It's nonsensical.
Periods don't even coincide with either ovulation or the creation of embryos. Periods happen about two weeks after ovulation, and typically only if there is no embryo to nourish.
If your parents did anything different at all the night you were conceived you wouldn't exist. But someone else most likely would! There were 100 million sperm so even the tiniest change and another one would have made it to the egg first. And someone else would exist and you would not.
An embryo outside the body can't develop unless someone makes a choice. So, to me, they aren't really that different from a sperm and an egg. Just like you exist because your parents decided to get it on at that exact millisecond, so two those embryos can't exist unless someone decides to implant them.
I mean....they do exist though. They cant develop unless someone decides to implant them, but they were created and by your own choice. I can understand why someone would feel some responsibility for life that they created through their own deliberate choice, but then chose not to allow to develop to their full potential.
To me the moral aspect is - can they become a person on their current natural trajectory? If it's safely implanted in a uterus then there is a very clear natural path towards personhood. To decide to interrupt that process when a natural path exists is morally problematic to me. But if a someone needs to intervene to put them on the natural path toward personhood then not doing that isn't morally problematic for me.
In short, what happens if you do nothing.
Implanted embryo? Person.
Embryo in a dish? Not person.
If your child in in a natural trajectory towards starvation, are you free from any obligation to help them?
They are already a person.
That's my point, you value people for their personhood, not their road-to-personhood
Yeah, I find conception as a cutoff to not really be consistent due to the nonviability of a wombless zygote. Gametogenesis as a cutoff ("if you can conceive and feed a child you have a moral duty to do so") and implantation as a cutoff ("abstinence, rhythm, condoms, implantation blockers and selective IVF are fine; abortion of an implanted pregnancy is not") are both consistent positions to take, but in-between doesn't really work.
I don't follow: yes, a womb-less zygote will die, but so will a baby who doesn't have anyone around to feed it. Yet nobody argues that the baby has no moral worth because it is dependent on a third party for continued existence, so why should that standard apply to the zygote?
>Yet nobody argues that the baby has no moral worth
False. I do.
However, I am not arguing my own position here; I'm arguing which positions are consistent. As such, that is irrelevant. So:
The dependency of human development on implantation is not merely one of nutrients; it's a marker that activates a whole pile of genetic switches. You can give a blastocyst all the nutrients it wants, but it won't develop beyond that stage. As such, the assembly criterion ("recipe complete, just add food") often given as a justification for conception as a cutoff is only really satisfied at implantation.
There are consistent positions which would make a zygote sacred - but those positions also make ova and spermatozoa sacred, because the partial assembly of the two is the only difference.
Where would you get that many parents?
I feel like I might as well chime in with my perspective, as someone who has done pre-conception genetic screening for myself and my partner (through Dor Yeshorim) and is currently 7 months pregnant with (hopefully) my first child after IVF (with ICSI). Upfront: I would not consider polygenic screening of embryos for future pregnancies as the technology stands, and only a few specific improvements would push me to reconsider.
Re: Dor Yeshorim, my husband and I checked and were deemed “a match” prior to engagement; that is, for a panel of recessive genetic disorders common in Ashkenazi Jewish background, we were mutual carriers for the disease alleles for none (Dor Yeshorim also offers testing for genetic disorders for non-Ashkenazi Jewish backgrounds, and other genetic testing services for those of Jewish background are available and have some advantages). This was something we both strongly believed offered an excellent cost/benefit ratio due to high background risk and severe disease for affected individuals. If we had been mutual carriers for one or more of these disorders, I expect we would have still married and used IVF with pre-implantation genetic screening for whatever we were mutual carriers for. So anyway, I don’t have a general objection to pre-conception genetic screening (which I used) or pre-implantation genetic screening. I ended up doing IVF in my 20s due to infertility.
When you do a round of IVF, you pay a fairly high price for a very limited number of embryos. I was in many ways an ideal candidate for IVF: at 27, young as these things go, good general health, no identified reproductive issues – only male factor infertility had been identified, and was likely the cause of our low fertility. At my fertility clinic, I paid about $20,000 as a flat fee for up to six egg retrieval and fertilization cycles and unlimited embryo transfers, until such time as I gave birth to a living, breathing baby. A single egg retrieval cycle and one or maybe more embryo cycles would have been somewhat cheaper, but two separate rounds of egg retrieval and fertilization ala carte would have been more expensive, and I couldn’t be sure that I’d succeed in a single round. That price doesn’t include the drugs, which are ballpark $3,000-$5,000 and in my case were substantially covered by our insurance. We did extremely well with our egg retrieval and fertilization: 16 eggs retrieved (just about the sweet spot for generating the highest number of good embryos in a single cycle; many more eggs and the overall quality starts to go down as far as I’ve read), 12 of these fertilized, 8 of those grew to five-day blastocyst embryos (all of which were graded highly, that is, they looked morphologically good under the microscope, which to my understanding at best correlates loosely to successful implantation). One cycle, $20,000, eight good embryos – basically the best-case scenario. Now, implantation – what are the odds there? Again, I’m in good general health, age 27, no ovulation or other reproductive cycle problems identified – and each fairly good-looking embryo transferred has slightly under 50% odds to come through as a living baby (slightly over 50% chance to implant, with about the normal rates of miscarriage or pregnancy loss). My first transfer (fresh, during the same cycle as the egg retrieval) didn’t take, my second (“natural cycle” frozen embryo transfer) did, and I’m now seven months pregnant with no major risk factors or complications.
-1/2-
I was a good IVF candidate and I’m not too squeamish of needles, blood draws, transvaginal ultrasounds, general anesthesia, so the burden of the procedures on me was on the low end. I have six frozen embryos generated at age 27, which are probably on average as good as I am likely to get because quality is expected to diminish with age, and risk of certain genetic mishaps is expected to increase (although for both, probably only marginally over the next few years). My husband and I might want, say, four kids. It’s certainly possible I could have three more healthy pregnancies out of our remaining six embryos, but not a guarantee; if we run out of embryos before we have as many kids as we want, I’ll probably have to do at least one more retrieval and fertilization cycle (preferably before too much more aging – I’d probably consider another round by age 32 if I’m not sure I won’t want more embryos for IVF). If I knew I only wanted one or maybe two kids and I had eight embryos to start with, maybe I’d feel like polygenic screening had some value, as I could expect that one of the top two or three scoring embryos would probably implant and be carried to term. But let’s say I were doing elective IVF for the purposes of polygenic screening and choosing the purportedly lowest risk for several health condition and I had four embryos. The chance that the best of four by polygenic screening fails to implant or results in an early miscarriage is about 50%. If it works, great, I can feel good that I selected an embryo with (possibly) a slightly lower lifetime risk of breast cancer or diabetes. What’s my threshold for the other three not being good enough to transfer and do another round of egg retrieval and fertilization, with associated costs, time, and physical burden (again, even granted that the physical burden on me was probably easier than average)? Consider that taking cells from the embryo for screening has a low but nonzero risk of reducing the viability of the embryo (to the best of my understanding). What if the best two or even three fail to implant?
I was offered genetic and other forms of screening several times, starting prior to IVF and through fertilization and pregnancy. My husband and I declined pretty much all of them. Mostly, I felt like I had done my due diligence in definitively ruling out the most likely (based on ethnic background) most debilitating genetic diseases. Most of what I was offered in terms of screening appeared to target genetic disorders we were very unlikely to carry, and the cost-benefit ratio didn’t seem to favor further screening. For me, some of it was accepting what I did and didn’t have control over by acknowledging that most of the screening offered much more of the illusion of control than actual benefit (which by my best judgment was marginal). I’m not buying into, well, copium. Here? The benefits are slightly lower lifetime risk of a few major health issues, if the polygenic scoring is really as good as purported. I tried looking up what the LifeView site had to offer about their polygenic scoring. The genomic index selection data is only validated for people of European descent, and appears to be generated from and tested on data from the UK Biobank in white European subjects only. That’s not validated in my background. Even if it were, for most of these, the differences are not meaningful to me as an individual who will have only a few kids – 2.6% risk of prostate cancer being reduced to 2.1% is not a meaningful lifetime difference in my eye in comparison to the cost, time, and physical burden. Others may well feel differently, of course. I am interested in what they have to say on polygenic scoring for embryos with an affected sibling or parent. So far they only have data available on this for type 1 diabetes.
Ultimately, I would absolutely not choose elective IVF for the purposes of polygenic screening with the quality of the data available.
What type of screening would I consider – what would bring the benefits up towards being commensurate with the costs and risks? My husband and I came out okay on screening for the genetic disorders we’re at higher risk for by ethnic background, but let’s say my husband and I were both carriers for cystic fibrosis and knew every embryo we generated had a 25% chance of having cystic fibrosis. I’d definitely choose elective IVF and embryo screening in that case. The cost-benefit assessment there seems well in favor of screening. So for polygenic screening, what would I be looking for? Screening with established effectiveness for a few heritable polygenic traits that my husband and I would expect to be at risk for – in our cases, depression, schizophrenia, and probably autism (a word on autism – three of my five siblings have ASD, including two who will probably never be independent adults due to their autism and/or comorbid behavioral issues that are very hard to tease apart from autism and/or exacerbated significantly by the communication challenges posed by autism. I love them just as I love my other siblings and don’t think they should be other than as they are, but no parent wants their child to have that type of barrier to any real form of adult independence, and autism as it has manifested in my immediate family seems to have a high risk for that outcome). For these items I think my children have elevated risk and I would expect more than marginal benefit from polygenic screening – given certain assumptions. At the very least I would want to know that the polygenic scoring for the trait in question has been validated in a population with sufficient data from my ethnic background. More ideally, I want to know if the screening is actually picking up anything that’s actually contributing to my personal risk. I’m not sure this is the way you would want to check this, but here’s my thought process: what is the risk assessment by polygenic scoring on the trait of interest for either parent? If the baseline risk assessed for me and/or my husband for a condition we have reason to believe we have or have risk of carrying substantial genetic contributions for is substantially elevated, it might offer enough information to be valuable to me. Let’s say depression – my husband and most of his immediate family have it, and I and multiple members of my immediate family have had it, either chronically or episodes that required medication. If my husband were given polygenic screening for depression and he scored pretty close to population average, well, that’s a screening that might be valuable in some context, and I would still assume he has highly heritable depression risk, but that test is probably not picking up a genetic signature that corresponds to his depression. So why should it pick up whether an embryo his sperm fertilized has a substantial contribution from his familial risk factors or not? I’d rather my child not have depression, but I can and will accept the baseline risks for depression and a host of other health conditions just like I do the risks for, say, birth defects. That’s something I can accept as part of reproduction; your mileage may vary. If I have reason to believe I’m at elevated risk for something, that may be something I want to control more – but only if my knowledge of elevated risk and the information I can get from polygenic scoring about the contribution to my embryo of the risk factors that bring me so much above baseline line up. On the topic of birth defects, current guidance is that IVF pregnancies have double the rate of birth defects of the heart – something like .7% for natural conception to 1.3% for IVF. It’s still a small absolute risk, but if you’re doing polygenic screening you’re 100% opting into IVF. That itself should be a major consideration to weigh against the current purported polygenic scoring benefits. Anyway, the benefits may well start to line up more with the costs and risks in the future (for my personal calculus, your mileage may vary). For now, this doesn’t even look like playing G-d; this looks like bargaining with RNGesus, and not at a very appealing rate.
Thanks for the detailed write up!
I take it the reference to rejecting genetic testing refers specifically to PGT-A (since it sounds like you didn’t have a need for PGT-M).
My understanding is that such testing net increases the likelihood of implantation (i.e. the selection effect less the biopsy effect is positive). Did your research indicate otherwise or was that just not an important consideration for you?
Not an important consideration for me based on my research given my age and my partner's age and the number of embryos generated (and the lack of difficulty in getting to the hormonally receptive state for implantation). My understanding is that the considerations are different mainly for IVF in women a decade or more older than me, who will tend to produce fewer embryos with higher likelihood of abnormalities. Even then my understanding is that the main benefit is knowing sooner whether they are likely to need to try another retrieval cycle to generate an embryo with a reasonable chance at success, because waiting around has an even harsher effect on expected embryo generation difficulty. If I had fewer embryos generated I might have made a different choice. As it stood, my embryos were expected to be of a good enough average quality to get what I wanted, and I was more interested in saving the money and effort.
Thanks for writing this, this was interesting.
I'm in a similar situation, but different enough that I think it changes the calculus: I'm doing elective egg freezing just to keep my fertility options open when I'm older, and I'm doing several cycles because I'm paranoid that I'll get weirdly unlucky and/or I'll want a lot of kids. So, at some point I'm going to have ~25 embryos to choose from, at which point polygenic screening starts to look pretty good, especially as it gets better in the next decade or 2. And I've already accepted that I have to do IVF as the cost of delayed child-rearing. I admit the "freeze a crap ton of eggs (or embryos) when you're young, just in case" strategy probably isn't that common though.
How many egg cycles are you planning on to get to 25 embryos? I’d think it’d take 5ish.
This sets off so many alarm bells for me, but to pick just three issues that I haven't seen in the comments so far, this seems like another step down the road to:
- even more expensive and physically and emotionally grueling norms and expectations foisted on women who want to have children "responsibly"
- even more prejudice against disabled and sick people (for existing) and their parents (for allowing them to exist)
both within the medical establishment and in the broader culture
- even more division and acrimony between the socioeconomic classes...
In 2050 Africa is projected to have 2.5 billion people. Presumably very few of them will be able to afford any sort of these genetic tests (to say nothing of poor people elsewhere in the world). And millions (possibly billions) of people will have moral objections to using IVF. If there isn’t enough resentment of elites now, just imagine what will happen after a few generations of selecting embryos for intelligence, health, looks, personality, etc. (Hopefully they can find the genes for humility soon, or else things might get really ugly.)
You can make a parallel argument for the advent of mechanized farm equipment (or proabably any technological advance), ie. more emotionally and physically gruelling norms for non-mechanized farm workers to keep up, more prejudice against human farm owners that refuse to get with the times, more division and acrimony between classes that can/cannot afford mechanical devices, etc.
In fact, we now see the exact opposite: people are valuing organic and hand-made crafts over mechanized products. Humans are not always easily predicted. Of course your points are something to consider for sure, but they strike me as pretty weak predictors and no reason to halt progress.
https://www.statnews.com/2021/07/01/researchers-raise-concerns-genetic-risk-scores-pick-healthier-embryos/?utm_content=bufferd4781&utm_medium=social&utm_source=twitter&utm_campaign=twitter_organic
To pay for the treatment it should be legal for potential parents to borrow the money and obligate their future child to pay back the loan.
Ah, yes, the many people willing to loan to the developing world... who can then hand their future children debt burdens to work off, as opposed to the richer IVF babies who will have nothing to work off.
This is a very "head up the ass" solution. Maybe "micro gene loans?" https://www.npr.org/sections/goatsandsoda/2016/11/01/500093608/you-asked-we-answer-can-tiny-loans-lift-women-out-of-poverty How about we allow the IVF treatments to be infinitely divisible, so you can get, perhaps, *one* gene instead of all of them so you can build up your polygene scores over generations?
Now that's what I call a road to serfdom
If you search on YouTube or look on his blog information processing Steve has some good talks on the ability to predict IQ.
Personally, I think that's far from the most important thing. The ability to select against things like disposition to have depression could be huge!
PRS screens are a perfect scam: no proof that they are effective, and no way to prove that they are ineffective for adult onset diseases like schizophrenia for at least 18 years. Go capitalism!
I've been waiting for this post. Some quick numbers I ran the other day to give a clearer sense of how cost-effective polygenic screening is.
Type 2 Diabetes is one of the more common condition for which we have decent polygenic tests. [One study estimated that 40% of Americans will develop type 2 diabetes at some point in their life](https://www.webmd.com/diabetes/news/20140812/40-percent-of-americans-will-develop-diabetes-cdc-projects). The number of years of life lost to type 2 diabetes varies quite a bit depending on the age at which one develops the condition, but [this study found that even among older men and women, they lost 11.1 and 13.8 Quality Adjusted Life Years respectively.](https://jamanetwork.com/journals/jama/fullarticle/197439). This article suggests the average age of onset of Type 2 Diabetes is [45 years](https://www.medicalnewstoday.com/articles/317375), though the "source" here is just a caption under an image, so take this with a grain of salt. Regardless, let's assume that 15 QALYs is a reasonable estimate for the number of years lost by Type 2 Diabetics.
The value of a QALY varies, but [this article suggests that in the US we value a QALY at somewhere between $50k-$150k. Let's use a fairly conservatie estimate here of $50k.
The average US diabetic in 2013 spent [$85,000](https://pubmed.ncbi.nlm.nih.gov/23953350/) in direct medical costs over a lifetime (about $100,000 in today's dollars).
Add these two up, and Type 2 Diabetes costs the average American diabetic $835,000. With a 4 in 10 chance of getting type 2 diabetes at some point in one's life, the average future American will lose $334k to type 2 diabetes.
Using [Shai Carmi et al](https://github.com/scarmi/embryo_selection)'s code for estimating the relative risk reduction from selecting the two best embryos out of a batch of 10 for a disease with prevalence of 0.4, whose variance we can explain roughly 11% of with polygenic testing, it looks like the first embryo would get an expected risk reduction of 13.7%, while the second would (probably) get a risk reduction of around 10%. At $835,000 of lifetime costs, this works out to a total value of about $200,000 just for Type 2 Diabetes risk. It's possible the 40% lifetime risk I found in the article linked above is high. But even if the risk is only 20%, it's still worth $136k. And the true value is likely to be higher because adding more traits will always increase the expected value.
[CNY sells normal IVF services for $16,000](https://www.cnyfertility.com/ivf-cost/). With a $1400 starting fee and a $400/embryo screening fee (the cost last time I checked in on LifeView), the additional cost from screening would be $5400, bringing the total to $21400. In other words, you could pay $21,400 to get a lifetime benefit of $200,000 for your children. For a life of 85 years, that works out to a 2.7% annual return by the time your children die (though it's likely the return would be somewhat better if we included other diseases).
There's something to be said for the non-fungibility of health. The most expensive medical care in the world can only do a limited amount to extend the lifespans and improve the health of diabetics. And the same is true for nearly all chronic conditions that can be screened for with polygenic testing. So even if you skipped IVF + polygenic screening for your children and invested $21k into index funds, the $6 million valuation it would have by the time your children reached retirement age probably couldn't be turned into an additional 5 years of healthy life.
Your estimate for IQ gain is actually off: using results from [EA3](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985927/), we can explain roughly 10% of variance in intelligence from genetic testing. Using Gwern's own code, we can estimate a gain of 5.5 IQ points when selecting the best of 10 embryos. I suspect Gwern was using results from EA2, which only explained 4.5% of variance. With 34 embryos (the amount the couple in the article you linked had to choose from), we would expect a gain of roughly 7.4.
My overall conclusion is that if we somehow end up banning pre-implantation genetic testing it will be one of the worst decisions we have ever made. The impact would be on-par with a worldwide ban on vaccines or sewage systems. It would likely cost the average person around 5 years of healthy life. In fact I think it will be so bad for the citizens of a country that anyone who can afford to will probably leave to get it done elsewhere, since the cost of the plane flights to get IVF done will be trivial compared to the lifetime benefits of reducing polygenic disease risk.
And the math looks more compelling the further out we extrapolate. There's several research labs working on creating egg cells from induced pluripotent stem cells, which in turn can be created from skin or blood cells. If someone manages to get that working it may eliminate two of the biggest drivers of IVF cost: medication to stimulate egg production and surgical extraction of the eggs by a specialist doctor. Producing and screening embryos at that point would be as simple as submitting a cheek swab and a sperm sample and signing some consent forms. The only remaining necessary procedure would be frozen embryo transfer, which is typically less than $1000.
At that sort of price level I suspect we would see embryo screening become a routine part of pre-pregnancy care. Every generation would have lower chronic disease risks, higher healthy life expectancies and greater intelligence. At least it might continue for a few generations before we hit the singularity. After that who knows what will happen.
Hello Gene, my name is Laurent, I'm the CEO of Genomic Prediction. We've been doing a similar calculation, using similar methodology. Would you be interested in contacting me to discuss a potential collaboration? contact@genomicprediction.com
Why would you sum the risk reductions of the two embryos?
Most parents have around two kids. It seems likely that parents who go through IVF to reduce their child's disease risk are likely to have all of their kids through the process. So it makes sense to assume they will implant the two embryos with the lowest risk of disease.
Ah right, thanks - I didn't realize embryo freezing was a possibility! Funny to think that there are people who were conceived years before their birth.
It may be worth saying explicitly that from "polygenic testing and picking best-of-10 will on average reduce the risk of type 2 diabetes by 14%" and "polygenic testing and picking best-of-10 will on average increase IQ by 5 points" it _doesn't_ follow that polygenic testing and picking best-of-10 will on average reduce the risk of type 2 diabetes by 14% _and_ increase IQ by 5 points. You can pick one or the other, or some combination of both that does both less effectively, but you can't get them both at once. Screening for more traits will let you do more, but never all that much: by any criterion of "best", the best of 10 embryos from a given pair of parents isn't likely to be _that much_ "better" than the average from the same pair. And, given that some embryos fail to implant, actually it's just as likely to be the second-best or maybe the third-best.
(I'm not specifically saying that PGS shouldn't be done or isn't worth it, just cautioning against combining figures overoptimistically.)
The paragraph that starts with "My overall conclusion" does not actually follow from anything you wrote above; your analysis merely told you how to gain like 2.7% interest rate on $20k, which is not all that much. One might easily read your analysis and conclude that IVF is not worth it, then you conclude it's a better invention than SEWAGE SYSTEMS?!?
I can't believe Scott linked to this nonsense.
To pour some cold water on all this hype: IVF caries risks, risks that everyone involved in these discussions seems to ignore. Other than the risks and discomforts to the mother from the procedure, IVF babies have more of most types of defects and diseases. Now, we don't know whether IVF, when performed on normal-fertility women, results in a decrease in health of the baby; maybe it's all confounders. But everyone knowledgeable only recommends to do genetic screening IF YOU ARE ALREADY DOING IVF FOR OTHER REASONS.
I am not aware of anyone knowledgeable that recommends IVF+genetic screening for mothers with no fertility issues who can conceive without IVF. Gwern himself does not recommend this.
Agree with LGS' concern about the overall conclusion. I do appreciate the effort that went into the post and it seems plausible IVF is highly valuable. But effort that can justify a weaker claim is no reason to make extreme claims without further evidence.
The conclusion clearly does not follow from the content in the post. Even on the most optimistic mentioned assumptions, 15 QALY lost to diabetes on average, 40% diabetes incidence, 15% reduction by IVF screening, *100% of people in the world getting IVF* we only get 0.9 QALY average increase. Still great, but not 5 years.
Maybe a lot more could be gotten from screening against other diseases too. And presumably that's where the 5 year idea comes from?
But note on the other hand that there are studies estimating that curing *all* cancer and heart disease - the two biggest killers- would only give us 6 more years to live. Given that it seems highly unlikely IVF could get that far. See https://www.latimes.com/archives/la-xpm-1990-11-02-mn-3743-story.html
Preimplantation genetic diagnosis (PGD) has been in use for years, and many children have been born thanks to it. With that in mind, how is last year's birth of "Aurea Smigrodzki" through preimplantation genetic testing for polygenic (PGT-P) significant?
I've never seen "PGT-P" before, and Google didn't reveal any sources that explained how it was different from PGD.
PGT-P can screen for a much much wider variety of traits. Previous PGD really only looked at chromosomal abnormalities like Down Syndrome and single-gene genetic disorders like Sickle Cell Anemia and Tay Sachs. PGT-P can assess heart attack risk, breast cancer risk, diabetes risk and others.
The tests they use for this still only explain ~10% of variance for most traits, but this is enough to get a 50-60% reduction in the risk of a single disease when selecting from among 10 embryos (or 20-30% for several diseases when selecting for lower risk of multiple diseases).
With a name like "Gene Smith," you should get a job doing PGT-P!
This might be a dumb question, but PGT-P also screens for all the disorders PGD detected, right? If Yes, then is PGD obsolete?
PGT-P is a subset of PGD. PGD emcompasses all types of genetic testing. Traditionally that included aneuploidy testing (down syndrome etc), monogenic disease testing (sickle cell anemia, Huntington's, Tay-Sachs etc). Recently companies have started offering miscarriage risk, structural rearrangement testing, polygenic disease testing. But they're all PGD.
Do you have a source for that? I can't find that info anywhere.
As I haven't seen it linked elsewhere here is a recent review of the limitations and misunderstanding of PRS from Lior Pachter: https://liorpachter.wordpress.com/2021/04/12/the-amoral-nonsense-of-orchids-embryo-selection/
tl/dr PRS is usually misunderstood, as are the percent reduction in complex traits.
Full disclosure, I believe human life (and personhood) begins at conception. So the whole concept of deliberately creating lots of people in order to pick one and kill the rest is pretty horrifying to me.
But for the rest of you, consider this issue. What happens when the parents who paid thousands of dollars to pick the "perfect child" discover that their child is just as human and imperfect as the rest of us?
Also, try listening to the adult children of donor conception and IVF. A lot of them do not appreciate being purchased.
FYI, IVF works by selecting embryos *before* conception, then choosing a specific one to implant sperm into. Each embryo is about as much as a person as a woman's period is (that is to say, by most moral systems, not at all.) If IVF was sex-selective abortion it would be far more of a culture-war flashpoint.
Surely this can't be right. (At least, not if talking about the sort of polygenic screening discussed here.) Before conception, what you have isn't an embryo, it's separate eggs and spermatozoa. When they say "pre-implantation" it doesn't mean "before implanting sperm into egg", it means "before implanting fertilized egg into uterus". I guess you can do a bit of genetic screening on unfertilized eggs, but it will be much less effective than doing it on fertilized ones, and e.g. all the calculations Gene Smith did above are assuming that it's fertilized eggs -- embryos -- that are subject to screening.
It's true, and interesting, that IVF attracts much less anger than (ordinary) abortion. But e.g. the Roman Catholic Church officially condemns IVF, and so do at least some evangelicals.
Oh wow, I did not realize that. Had always assumed that IVF was pre-implantation and that it was easy to simulate the genes of the resultant embryo caused by implanting a specific sperm into a specific egg. If genetic screening on unfertilized eggs is much less effective, why?
Actually, I don't know whether it's even _possible_. You'd need to read out all the contents of the egg's DNA without damaging the egg, which sounds impossible to me, and do the same for the sperm, which sounds even more impossible.
What they actually do is to _remove one cell from an embryo_ and look at its DNA. I'm pretty sure this destroys that cell, but the process of embryo development doesn't seem to be disrupted as a result.
It's possible as the egg drops chromatids it extra cells to bring it down to 23 chromosomes. It's actually being done regularly.
Are you talking about using polar bodies for screening? That works, but it only lets you see half the genome.
If you don't kill the rest, and instead keep them frozen indefinitely, no one is being killed.
"Also, try listening to the adult children of donor conception and IVF. A lot of them do not appreciate being purchased."
Links?
Like Nancy, I would be interested in more information about these "adult children of donor conception and IVF" and what exactly it is they object to. So far as I can tell, most people in that situation are as glad to be alive as anyone else, and I don't see how they're "purchased" any more than (say) someone who would have died shortly after birth if it weren't for a hospital's (possibly expensive) neonatal intensive care unit.
As for your question: if anyone thinks they're picking a "perfect child" or a child who's something more than human, then they're either being deceived or deceiving themselves, and in that situation they're liable to be disappointed. But "it's possible for people to be deceived about X and then disappointed" is no argument against X, because it's true for _everything_.
What a more reasonable parent might think, if the sort of thing discussed here becomes common, is that their children are _less likely_ to (say) develop diabetes than they would have been with a more traditional conception process. In that case, your argument has the same structure as this. "What happens when, having paid thousands of dollars more for a more reliable car, it breaks down anyway?". The answer, obviously, is that (1) when that happens you'll be disappointed, but (2) when it _doesn't_ happen you'll be glad, and the hope is that the thousands of dollars make #2 happen more often and #1 happen less often. Similarly, if you pay thousands of dollars in the hope that your child will be less likely to get diabetes, then (1) if they do you'll be disappointed and (2) if they don't you'll be glad, and the hope is that _on balance_ the embryo-selection thing makes #2 more likely and #1 less likely.
(Maybe it will turn out that it doesn't work so well. In that case few will be willing to put up with the cost and inconvenience. And maybe it'll work fine but be the moral equivalent of mass murder. In that case we shouldn't do it, but it seems most people don't agree with you on that point, and for what it's worth I also don't. I will, like you, refrain from getting into an argument about that contentious question, but I will suggest that you consider the folllowing thought experiment: Suppose that at one of these clinics there is a fire, and a nurse carrying a tray full of newly fertilized embryos is in danger of not getting out before the flames overwhelm the building. Which would be the greater tragedy: for the nurse to get out with the tray of embryos and then die of her burns, or for the nurse to leave the tray of embryos behind but get out safely?)
Worry about large-scale ill effects of gene screening seems to be based on an assumption that there will be a consensus about what gets screened. My bet is that if there is large-scale screening, there will be a number of organizations doing it and in the nature of things, they won't all be using the same screens. They might even go about screening for the same genes in different ways with different effects. Does this take some of the edge off?
https://m.youtube.com/watch?v=HE5ADe7BgdM
https://www.ivfbabble.com/on-the-40th-anniversary-of-the-first-ivf-in-the-usa-the-first-baby-elizabeth-jordan-carr-looks-at-how-science-today-has-produced-a-new-world-first-baby-aurea
Yes, this is my daughter Aurea's photograph, not stock. Thanks for writing about polygenic testing, this is a revolutionary medical technology and yet many oppose it. Note: I do not have any commercial or professional involvement with PGT-P, my GF and I just happened to be the first couple to successfully use the technology. The more parents know about it, the sooner it becomes standard medical practice, which is a good thing, since (as I see it) it leads to Lake Wobegon, not to GATTACA.
Incredible, thank you. Are there any new photos of Aurea?
Yes, there are lots of new photos, she gets cuter all the time.
Share?
See picture here https://whyy.org/segments/startup-offers-genetic-testing-that-promises-to-predict-healthiest-embryo/
This is great! Congratulations, Rafal!
Should I delay having children to take advantage of polygenic screening?
x-post: https://www.lesswrong.com/posts/tg2fzDSjzyEgo2QFr/should-i-delay-having-children-to-take-advantage-of
Most parents raise two or more children. It appears likely that parents who use IVF to lower their child's risk of disease will probably use the procedure for all of their children. Therefore, it stands to reason that the two embryos with the lowest chance of illness will be implanted.
https://medium.com/@zulkaifrana52/discover-the-best-baby-bottles-for-breastfed-babies-an-in-depth-review-05eefe13d7b5